Aryloxyalkylamine derivatives as h3 receptor ligands

ABSTRACT

The present invention relates to novel benzyloxy derivatives having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of neurological and psychiatric disorders.

The present invention relates to novel phenoxy derivatives havingpharmacological activity, processes for their preparation, tocompositions containing them and to their use in the treatment ofneurological and psychiatric disorders.

WO 02/76925 (Eli Lilly), WO 00/06254 (Societe Civile Bioprojet), WO01/66534 (Abbott Laboratories) and (WO 03/004480 (Novo Nordisk) describea series of compounds which are claimed to be histamine H3 antagonists.WO 02/40466 (Ortho McNeill Pharmaceutical) disclose a series ofamido-alkyl piperidine and amido-alkyl piperazine derivatives which areclaimed to be useful in treatment of various nervous system disorders.

The histamine H3 receptor is predominantly expressed in the mammaliancentral nervous system (CNS), with minimal expression in peripheraltissues except on some sympathetic nerves (Leurs et al., (1998), TrendsPharmacol. Sci. 19, 177-183). Activation of H3 receptors by selectiveagonists or histamine results in the inhibition of neurotransmitterrelease from a variety of different nerve populations, includinghistaminergic and cholinergic neurons (Schlicker et al., (1994), Fundam.Clin. Pharmacol. 8, 128-137). Additionally, in vitro and in vivo studieshave shown that H3 antagonists can facilitate neurotransmitter releasein brain areas such as the cerebral cortex and hippocampus, relevant tocognition (Onodera et al., (1998), In: The Histamine H3 receptor, edLeurs and Timmerman, pp255-267, Elsevier Science B.V.). Moreover, anumber of reports in the literature have demonstrated the cognitiveenhancing properties of H3 antagonists (e.g. thioperamide, clobenpropit,ciproxifan and GT-2331) in rodent models including the five choice task,object recognition, elevated plus maze, acquisition of novel task andpassive avoidance (Giovanni et al., (1999), Behav. Brain Res. 104,147-155). These data suggest that novel H3 antagonists and/or inverseagonists such as the current series could be useful for the treatment ofcognitive impairments in neurological diseases such as Alzheimer'sdisease and related neurodegenerative disorders.

The present invention provides, in a first aspect, a compound of formula(I) or a pharmaceutically acceptable salt thereof:

wherein:

-   R¹ represents a group of formula (A):    wherein R^(4a) represents C₁₋₆alkyl, oxo, aryl, heteroaryl or    heterocyclyl; R^(5a) represents hydrogen, -C₁₋₆ alkyl,    -C₁₋₆alkylC₁₋₆alkoxy, -C₁₋₆alkoxycarbonyl, -C₃₋₈ cycloalkyl, -aryl,    -heterocyclyl, heteroaryl, -C₁₋₆ alkyl-aryl, —CH(aryl)(aryl), -C₁₋₆    alkyl-Cm cycloalkyl, -C₁₋₆ alkyl-heteroaryl or -C₁₋₆    alkyl-heterocyclyl, wherein R^(5a) may be optionally substituted by    one or more (eg. 1, 2 or 3) substituents which may be the same or    different, and which are selected from the group consisting of    halogen, hydroxy, cyano, nitro, oxo, haloC₁₋₆ alkyl,    polyhaloC₁₋₆alkyl, haloC₁₋₆ alkoxy, polyhaloC₁₋₆alkoxy, C₁ alkyl,    C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ alkoxyC₁₋₆alkyl, C₃₋₇    cycloalkylC₁₋₆ alkoxy, C₁₋₆alkanoyl, C₁₋₆ alkoxycarbonyl, C₁₋₆    alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyloxy, C₁₋₆    alkylsulfonylC₁₋₆ alkyl, C₁₋₆ alkylsulfonamidoC₁₋₆ alkyl, C₁₋₆    alkylamidoC₁₋₆alkyl or a group NR^(15a)R^(16a), —CONR^(15a)R¹⁶,    —NR⁵²COR^(16a), NR^(15a)SO₂R^(16a) or —SO₂NR^(15a)R^(16a), wherein    R^(15a) and R^(16a) independently represent hydrogen, C₁₋₆ alkyl,    aryl or together with the nitrogen to which they are attached may    form a nitrogen containing heterocyclyl group;-   m is 1 or 2;-   p is 0, 1, 2 or 3, or when p represents 2, said R^(4a) groups may    instead form a bridging group consisting of one or two methylene    groups;-   or R¹ represents a group of formula (B):    -   wherein NR^(4b)R^(5b) represents an N-linked -heterocyclyl,        -heterocyclyl-X^(b)-aryl, -heterocyclyl-X^(b)-heteroaryl,        -heterocyclyl-X^(b)-heterocyclyl, -heteroaryl,        -heteroaryl-X^(b)-aryl, -heteroaryl-X^(b)-heteroaryl or        -heteroaryl-X^(b)-heterocyclyl group; wherein said aryl,        heteroaryl and heterocyclyl groups of NR^(4b)R^(5b) may be        optionally substituted by one or more (eg. 1, 2 or 3)        substituents which may be the same or different, and which are        selected from the group consisting of halogen, hydroxy, cyano,        nitro, oxo, haloC₁₋₆ alkyl, polyhaloC₁₋₆ alkyl, haloC₁₋₆ alkoxy,        polyhaloC₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆alkoxy, arylC₁₋₆ alkoxy,        C₁₋₆ alkylthio, C₁₋₆ alkoxyC₁₋₆ alkyl, C₃₋₇ cycloalkylC₁₋₆        alkoxy, C₁₋₆ alkanoyl, C₁₋₆alkoxycarbonyl, arylC₁₋₆ alkyl,        heteroarylC₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl,        C₁₋₆ alkylsulfonyloxy, C₁₋₆ alkylsulfonylC₁₋₆ alkyl,        arylsulfonyl, arylsulfonyloxy, arylsulfonylC₁₋₆alkyl, aryloxy,        C₁₋₆alkylsulfonamidoC₁₋₆alkyl, C₁₋₆ alkylamidoC₁₋₆alkyl,        arylsulfonamido, arylaminosulfonyl, arylsulfonamidoC₁₋₆ alkyl,        arylcarboxamidoC₁₋₆alkyl, aroylC₁₋₆alkyl, arylC₁₋₆ alkanoyl, or        a group —NR^(15b)R^(16b), —CONR^(15b)R^(16b), NR^(15b)COR^(16b),        —NR^(15b)SO₂R^(16b) or —SO₂NR^(15b)R^(16b), wherein R^(15b) and        R^(16b) independently represent hydrogen or C₁₋₆ alkyl;-   X^(b) represents a bond, CO, NHCO or CONH;-   or R¹ represents a group of formula (C):    -   wherein R^(4c) represents C₁₋₆ alkyl, OH, aryl or heterocyclyl,        wherein said aryl and heterocyclyl groups may be optionally        substituted by halogen, C₁₋₆alkyl, C₁₋₆alkoxy, cyano, amino,        oxo, trifluoromethyl or an aryl group;-   r is 0, 1 or 2;-   or R¹ represents a group of formula (D):    wherein R^(4d) represents aryl or heteroaryl wherein said aryl and    heteroaryl groups may be optionally substituted by one or more (eg.    1, 2 or 3) substituents which may be the same or different, and    which are selected from the group consisting of halogen, C₁₋₆alkyl,    C₁₋₆alkoxy, cyano, amino or trifluoromethyl;-   X^(d) represents a bond or NHCO, such that when X^(d) represents    NHCO, the group R^(4d)-X^(d) is attached at the 3-position of the    pyrrolidinyl ring;    -   or R¹ represents a group of formula —CO-E, wherein E represents        a group of formula E^(a), E^(b) or E^(c):        wherein X^(e) represents O or N—R^(8e);-   Y^(e) represents —C(HR^(9e))— or —C(═O)—;-   R^(4e), R^(5e), R^(8e) and R^(9e) independently represent hydrogen,    C₁₋₆ alkyl, aryl, heteroaryl, -C₁₋₆alkyl-aryl or -C₁₋₆    alkyl-heteroaryl;-   R^(6e) and R^(7e) independently represent hydrogen, C₁₋₆ alkyl,    aryl, heteroaryl, -C₁₋₆ alkyl-aryl, -C₁₋₆ alkyl-heteroaryl or R^(6e)    and R^(7e) together with the carbon atoms to which they are attached    may form a benzene ring;-   is a single or double bond;-   wherein said aryl or heteroaryl groups of R^(4e), R^(5e), R^(6e),    R^(7e), R^(8e) and R^(9e) may be optionally substituted by one or    more (eg. 1, 2 or 3) substituents which may be the same or    different, and which are selected from the group consisting of C₁₋₆    alkyl, CF₃, C₁₋₆ alkoxy, halogen, cyano, sulfonamide or C₁₋₆    alkylsulfonyl;-   or R¹ represents a group of formula (F):-   wherein t is 0, 1 or 2;-   u is 1 or 2;-   R^(4f) represents C₁₋₆ alkyl or when t represents 2, said R^(4f)    groups may instead form a bridging group consisting of one or two    methylene groups;-   R^(5f) represents -C₁₋₆ alkyl, -C₁₋₆ alkylC₁₋₆ alkoxy, -C₃₋₄    cycloalkyl, aryl, heterocyclyl, heteroaryl, -C₁₋₆ alkyl-aryl, -C₁₋₆    alkyl-C₁₋₆cycloalkyl, -C₁₋₆ alkyl-heteroaryl, -C₁₋₆    alkyl-heterocyclyl, -aryl-aryl, -aryl-heteroaryl,    -aryl-heterocyclyl, -heteroaryl-aryl, -heteroaryl-heteroaryl,    -heteroaryl-heterocyclyl, -heterocyclyl-aryl,    -heterocyclyl-heteroaryl or -heterocyclyl-heterocyclyl;-   wherein R^(5f) may be optionally substituted by one or more (eg. 1,    2 or 3) substituents which may be the same or different, and which    are selected from the group consisting of halogen, hydroxy, cyano,    nitro, oxo, haloC₁₋₆ alkyl, polyhaloC₁₋₆ alkyl, haloC₁₋₆ alkoxy,    polyhaloC₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆    alkoxyC₁₋₆ alkyl, C₃₋₇ cycloalkylC₁₋₆ alkoxy, C₁₋₆ alkanoyl, C₁₋₆    alkoxycarbonyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆    alkylsulfonyloxy, C₁₋₆ alkylsulfonylC₁₋₆ alkyl, C₁₋₆    alkylsulfonamidoC₁₋₆ alkyl, C₁₋₆ alkylamidoC₁₋₆ alkyl, arylsulfonyl,    arylsulfonyloxy, aryloxy, arylsulfonamido, arylcarboxamido, aroyl,    or a group NR^(15f)R^(16f), —CONR^(15f)R^(16f), —NR^(15f)COR^(16f),    —NR^(15f)SO₂R^(16f) or —SO₂NR^(15f)R^(16f), wherein R^(15f) and    R^(16f) independently represent hydrogen or C₁₋₆ alkyl or together    form a heterocyclic ring;-   Z^(f) represents CO or SO₂;-   R² represents halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cyano, amino or    trifluoromethyl;-   n is 0, 1 or 2;-   R³ represents —(CH₂)_(q)—NR¹¹R¹² or a group of formula (i):    wherein q is 2, 3 or 4;-   R¹¹ and R¹² independently represent Con alkyl or together with the    nitrogen atom to which they are attached represent an N-linked    heterocyclic group selected from pyrrolidine, piperidine and    homopiperidine optionally substituted by one or two R¹⁷ groups;-   R¹³ represents C₁₋₆ alkyl, C₃₋₆cycloalkyl or    -C₁₋₄alkyl-C₃₋₆cycloalkyl;-   R¹⁴ and R¹⁷ independently represent halogen, C₁₋₆alkyl,    haloC₁₋₆alkyl, OH, diC₁₋₆-alkylamino or C₁₋₆alkoxy;-   f and k independently represent 0, 1 or 2;-   g is 0, 1 or 2 and h is 0, 1, 2 or 3, such that g and h cannot both    be 0; or solvates thereof.

In one particular aspect of the present invention, when R¹ represents agroup of formula (F), R^(5f) is linked to Z^(f) via a carbon atom, urepresents 1 and Z^(f) represents CO.

Alkyl groups, whether alone or as part of another group, may be straightchain or branched and the groups alkoxy and alkanoyl shall beinterpreted similarly. Alkyl moieties are more preferably C₁₋₆ alkyl,eg. methyl or ethyl. The term ‘halogen’ is used herein to describe,unless otherwise stated, a group selected from fluorine, chlorine,bromine or iodine.

The term “aryl” includes single and fused rings wherein at least onering is aromatic, for example, phenyl, naphthyl andtetrahydronaphthalenyl.

The term “heterocyclyl” is intended to mean a 4-7 membered monocyclicsaturated or partially unsaturated aliphatic ring or a 4-7 memberedmonocyclic saturated or partially unsaturated aliphatic ring fused to abenzene ring containing 1 to 3 heteroatoms selected from oxygen ornitrogen. Suitable examples of such monocyclic rings includepyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, diazepanyl,azepanyl, dihydroimidazolyl, tetrahydropyranyl and tetrahydrofuranyl.Suitable examples of benzofused heterocyclic rings include indolinyl,isoindolinyl and tetrahydroisoquinolinyl.

The term “nitrogen containing heterocyclyl” is intended to represent anyheterocyclyl group as defined above which contains a nitrogen atom.

The term “heteroaryl” is intended to mean a 5-7 membered monocyclicaromatic or a fused 8-11 membered bicyclic aromatic ring containing 1 to3 heteroatoms selected from oxygen, nitrogen and sulphur. Suitableexamples of such monocyclic aromatic rings include thienyl, furyl,pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl,isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl,pyridazinyl, pyrazinyl and pyridyl. Suitable examples of such fusedaromatic rings include benzofused aromatic rings such as quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl,indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like.

Preferably, n represents 0.

Preferably, R³ represents —(CH₂)_(q)—NR¹¹R¹².

Preferably, q is 3.

Preferably, NR¹¹R¹² represents an N-linked heterocyclic group, morepreferably unsubstituted piperidine.

For compounds of formula (I) wherein R¹ represents a group of formula(A):

Preferably, R^(5a) represents:

-   -   hydrogen;    -   C₁₋₆ alkyl (eg. methyl or i-propyl) optionally substituted by        —CONR^(15a)R^(16a) (eg. CONMe₂, CONMe-phenyl, CO—N-piperidine or        CO—N-pyrrolidine);    -   C₁₋₆ alkoxycarbonyl (eg. t-butoxycarbonyl);    -   aryl (eg. phenyl) optionally substituted by one or more (eg. 1,        2 or 3) cyano, halogen (eg. fluorine or chlorine), C₁₋₆alkyl        (eg. methyl), C₁₋₆alkoxy (eg. methoxy), polyhaloC₁₋₆alkyl (eg.        trifluoromethyl) or C₁₋₆ alkanoyl (eg. COCH₃) groups;    -   heteroaryl (eg. pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,        quinolinyl or benzothiazolyl) optionally substituted by one or        more (eg. 1, 2 or 3) oxo, cyano, halogen (eg. chlorine), C, e        alkyl (eg. methyl) or polyhaloC₁₋₆ alkyl (eg. trifluoromethyl)        groups;    -   C₁₋₆ alkyl-heterocyclyl (eg. —CH₂-tetrahydrofuranyl);    -   C₃₋₈cycloalkyl (eg. cycloheptyl);    -   —C₁₋₆alkyl-heteroaryl (eg. —CH₂-pyridyl);    -   heteroaryl-aryl (eg. -thiadiazolyl-phenyl); or    -   —CH(aryl)(aryl) (eg. —CH(phenyl)(phenyl)).

Preferably, m represents 1.

When n represents 1, R² is preferably halogen (eg. fluorine) ortrifluoromethyl. When n represents 2, R² is preferably halogen (eg.fluorine).

Preferably, p represents 0, 1 or 2, more preferably 0.

When p represents 1, preferably R^(4a) represents oxo or C₁₋₆ alkyl (eg.methyl).

When p represents 2, preferably R^(4a) represents C₁₋₆alkyl (eg. methyl)or forms a methylene bridging group.

For compounds of formula (I) wherein R¹ represents a group of formula(B):

Preferably, NR^(4b)R^(5b) represents an N-linked heterocyclyl (eg.morpholinyl, piperidinyl, indolinyl, isoindolinyl or piperazinyl) or a-heterocyclyl_X^(b)-aryl group (eg. -piperidinyl-phenyl,-piperazinyl-phenyl, -piperazinyl-CO-phenyl or -piperazinyl-CO-naphthyl)optionally substituted by a polyhaloC₁₋₆alkoxy (eg. trifluoromethoxy)group.

For compounds of formula (I) wherein R¹ represents a group of formula(C): When present, R^(4c) preferably represents aryl (eg. phenyl), C₁₋₆alkyl (eg. methyl), OH or an optionally substituted heteroaryl group(eg. dihydroimidazol-2-one substituted by phenyl), more preferablyR^(4c) represents methyl.

When n represents 1, R² is preferably halogen (eg. fluorine) ortrifluoromethyl. When n represents 2, R² is preferably halogen (eg.fluorine).

When r represents 2, preferably R^(4c) represents methyl.

For compounds of formula (I) wherein R¹ represents a group of formula(D): Preferably, R^(4d) represents phenyl or naphthyl, more preferablyunsubstituted phenyl or naphthyl.

For compounds of formula (I) wherein R¹ represents a group of formula(E^(a)):

-   X^(e) is preferably O or NH, R^(4e) is preferably aryl (eg. phenyl)    or -C₁₋₆ alkyl-aryl (eg. benzyl) and Y^(e) is preferably —CH₂—.

For compounds of formula (I) wherein R¹ represents a group of formula(E^(b)):

-   R^(5e) is preferably aryl (eg. phenyl).

For compounds of formula (I) wherein R¹ represents a group of formula(E^(c)):

-   R^(6e) and R^(7e), together with the carbon atoms to which they are    attached preferably form a benzene ring and    is preferably a double bond.

For compounds of formula (I) wherein R¹ represents a group of formula(F):

Preferably, R⁵′ represents:

-   -   C₁₋₆alkyl (eg. i-propyl);    -   C₃₋₈cycloalkyl (eg. cyclohexyl or cycloheptyl);    -   aryl (eg. phenyl or tetrahydronaphthalene) optionally        substituted by a halogen atom (eg. chlorine), cyano,        N-propyl₂SO₂— or a polyhaloC₁₋₆ alkyl group (eg.        trifluoromethyl);    -   heteroaryl (eg. furyl, thienyl, pyridyl, quinoxaline, pyrazine,        1,2,3-benzothiadiazole, benzofuranyl, isoxazole or pyrazole)        optionally substituted by a halogen atom (eg. chlorine),        polyhaloC₁₋₆ alkyl group (eg. trifluoromethyl) or C₁₋₆ alkyl        (eg. methyl or t-butyl);    -   heterocyclyl (eg. morpholine, pyrrolidine, tetrahydrofuran or        tetrahydropyran);    -   C₁₋₆ alkyl-aryl (eg. α-methylbenzyl or α,α-dimethylbenzyl).

Preferably, R^(5f) is optionally substituted by one or more (eg. 1, 2 or3) halogen (eg. chlorine), cyano, trifluoromethyl, C₁₋₆alkyl (eg. methylor t-butyl), MeSO₂— or N-propyl₂SO₂ groups.

More preferably, R^(5f) represents C₃₋₈ cycloalkyl (eg. cyclohexyl),heteroaryl (eg. furyl) or aryl (eg. phenyl or tetrahydronaphthalene)optionally substituted by a cyano group.

Preferably, Z^(f) represents CO.

When n represents 1, R² is preferably trifluoromethyl.

Preferably, t represents 0 or 2, more preferably 0.

When t represents 2, both R^(4f) groups are preferably methyl or form amethylene bridging group.

Preferably, u represents 1.

When R³ represents a group of formula (i), preferably f represents 0, hrepresents 1, g represents 2, k represents 0 and R¹³ representsC₁₋₆alkyl (eg. isopropyl) or C₃₋₆ cycloalkyl (eg. cyclobutyl orcyclopentyl).

Preferred compounds according to the invention include examples E1-E172as shown below, or a pharmaceutically acceptable salt thereof.

Compounds of formula (I) may form acid addition salts with acids, suchas conventional pharmaceutically acceptable acids, for example maleic,hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic,sulphate, citric, lactic, mandelic, tartaric and methanesulphonic.Salts, solvates and hydrates of histamine H3 receptorantagoniststherefore form an aspect of the invention.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of these compounds and themixtures thereof including racemates. Tautomers also form an aspect ofthe invention.

The present invention also provides a process for the preparation of acompound of formula (I) or a pharmaceutically acceptable salt thereof,which process comprises:

-   -   (a) preparing a compound of formula (I) wherein R¹ represents a        group of formula (A) which comprises reacting a compound of        formula (II)        with a compound of formula (III)        or a protected derivative thereof, wherein R², R³, R^(4a),        R^(5a), m, n and p are as defined above and L is OH or a        suitable leaving group (eg. a halogen atom such as chlorine); or

-   (b) preparing a compound of formula (I) wherein R¹ represents a    group of formula (A) and wherein R³ represents —(CH₂)_(q)—NR¹¹R¹²    which comprises reacting a compound of formula (IV)    wherein R², R^(4a), R^(5a), m, n, p and q are as defined above and    L¹ represents a suitable leaving group such as a halogen atom (eg.    bromine) with a compound of formula HNR¹¹R¹²; wherein R¹¹ and R¹²    are as defined above; or

-   (c) preparing a compound of formula (1) wherein R¹ represents a    group of formula (B) which comprises reacting a compound of formula    (V)    with a compound of formula R^(4b)R^(5b)NH wherein R², R³, R^(4b),    R^(5b) and n are as defined above and L² is OH or a suitable leaving    group (eg. a halogen atom such as chlorine); or

-   (d) preparing a compound of formula (I) wherein R¹ represents a    group of formula (B) and wherein R³ represents —(CH₂)_(q)—NR¹¹R¹²    which comprises reacting a compound of formula (VI)    wherein R², R^(4b), R^(5b), n and q are as defined above and L³    represents a suitable leaving group such as a halogen atom (eg.    bromine) with a compound of formula HNR¹¹R¹²; wherein R¹¹ and R¹²    are as defined above; or

-   (e) preparing a compound of formula (I) wherein R¹ represents a    group of formula (B) which comprises reacting a compound of formula    (VII)    wherein R², R^(4b), R^(5b) and n are as defined above, with a    compound of formula R³-L⁴, wherein R³ is as defined above and L⁴    represents a suitable leaving group such as a halogen atom or an OH    group; or

-   (f) preparing a compound of formula (I) wherein R¹ represents a    group of formula (C) which comprises reacting a compound of    formula (II) as defined above, with a compound of formula (VIII)    or a protected derivative thereof, wherein R^(4c) and r are as    defined above; or

-   (g) preparing a compound of formula (I) wherein R¹ represents a    group of formula (C) and wherein R³ represents —(CH₂)_(q)—NR¹¹R¹²    which comprises reacting a compound of formula (IX)    wherein R², n, R^(4c), r, and q are as defined above and L⁵    represents a suitable leaving group such as a halogen atom (eg.    bromine) with a compound of formula HNR¹¹R¹²; wherein R¹¹ and R¹²    are as defined above; or

-   (h) preparing a compound of formula (I) wherein R¹ represents a    group of formula (D) which comprises reacting a compound of    formula (II) as defined above, with a compound of formula (X)    or a protected derivative thereof, wherein R^(4d) and X^(d) are as    defined above; or

-   (i) preparing a compound of formula (I) wherein R¹ represents a    group of formula (D) and wherein R³ represents —(CH₂)_(q)—NR¹¹R¹²    which comprises reacting a compound of formula (XI)    wherein R^(4d), X^(d), R², n, and q are as defined above and L⁶    represents a suitable leaving group such as a halogen atom (eg.    bromine) with a compound of formula HNR¹¹R¹²; wherein R¹¹ and R¹²    are as defined above; or

-   (j) preparing a compound of formula (I) wherein R¹ represents a    group of formula —CO-E^(a), —CO-E^(b) or —CO-E^(c) which comprises    reacting a compound of formula (II) as defined above, with a    compound of formula H-E^(a), H-E^(b) or H-E^(c) or a protected    derivative thereof, wherein E^(a), E^(b) and E^(c) are as defined    above; or    -   (k) preparing a compound of formula (I) wherein R¹ represents a        group of formula —CO-E and wherein R³ represents        —(CH₂)_(q)—NR¹¹R¹² which comprises reacting a compound of        formula (XII)        wherein R², n, q and E are as defined above and L⁷ represents a        suitable leaving group such as a halogen atom (eg. bromine) with        a compound of formula HNR¹¹R¹²; wherein R¹¹ and R¹² are as        defined above; or

-   (l) preparing a compound of formula (I) wherein R¹ represents a    group of formula (F) which comprises reacting a compound of    formula (II) as defined above, with a compound of formula (XIII)    or a protected derivative thereof, wherein R^(5f), Z^(f), R^(4f), u    and t are as defined above; or

-   (m) preparing a compound of formula (I) wherein R¹ represents a    group of formula (F) and wherein R³ represents —(CH₂)_(q)—NR¹¹R¹²    which comprises reacting a compound of formula (XIV)    wherein R^(5f), Z^(f), R², R^(4f), n, t, u and q are as defined    above and L⁸ represents a suitable leaving group such as a halogen    atom (eg. bromine) with a compound of formula HNR^(11a)R^(12a);    wherein R^(11a) and R^(12a) are as defined above for R¹¹ and R¹² or    a group convertible thereto; or

-   (n) preparing a compound of formula (I) wherein R¹ represents a    group of formula (F) which comprises reacting a compound of formula    (XV)    or a protected derivative thereof, wherein R², R³, R^(4f), n, t and    u are as defined above, with a compound of formula R^(5fa)-Z^(f)-L⁹,    wherein R^(5fa) is as defined above for R^(5f) or a group    convertible thereto, Z^(f) is as defined above and L⁹ represents a    suitable leaving group, such as a halogen atom (eg. chlorine) or a    hydroxy group which may be converted into a suitable leaving group;    and optionally thereafter

-   (o) deprotecting a compound of formula (I) which is protected; and    optionally thereafter

-   (p) interconversion to other compounds of formula (I).

Process (a) typically comprises halogenation of the compound of formula(II) with a suitable halogenating agent (eg. thionyl chloride) followedby reaction with the compound of formula (III) in the presence of asuitable base such as triethylamine or a solid supported amine, in asuitable solvent such as dichloromethane. Process (a) may also typicallycomprise activation of the compound of formula (II) with a couplingreagent such as dicyclohexylcarbodiimide or solid supported carbodiimidein a suitable solvent such as N,N-dimethylfonmamide followed by reactionwith the compound of formula (III).

Processes (b), (d), (g), (i), (k) and (m) are typically performed in thepresence of a suitable solvent (such as 1-butanol) at an elevatedtemperature.

Process (c) typically comprises reaction with the compound of formulaR^(4b)R^(5b)NH optionally in the presence of a suitable base such astriethylamine or a solid supported amine, in a suitable solvent such asdichloromethane. When L² represents OH, process (c) typically comprisesan initial halogenation reaction of the compound of formula (V) with asuitable halogenating agent (eg. thionyl chloride) prior to reactionwith the compound of formula R^(4b)R^(5b)NH as above.

Process (e) typically comprises an alkylation reaction under Mitsunobuconditions.

Processes (f), (h), (j) and (l) typically comprise reaction with thecompound of formula (VIII), (X), H-E^(a), H-E^(b), H-E^(c) or (XIII)optionally in the presence of a suitable base such as triethylamine or asolid supported amine, in a suitable solvent such as dichloromethane.When L represents OH, processes (f), (h), (j) and (l) typically comprisean initial halogenation reaction of the compound of formula (II) with asuitable halogenating agent (eg. thionyl chloride) prior to reactionwith the compound of formula (VIII), (X), H-E^(a), H-E^(b), H-E^(c) or(XIII) as above.

When L represents OH, processes (f), (h), (j) and (l) may also typicallycomprise activation of the compound of formula (II) with a couplingreagent such as dicyclohexylcarbodiimide or solid supported carbodiimidein a suitable solvent such as N,N-dimethylformamide followed by reactionwith the compound of formula (VIII), (X), H-E^(a), H-E^(b), H-E^(c) or(XIII).

Process (n) typically comprises the use of a suitable base, such astriethylamine or a solid supported base such asdiethylaminomethylpolystyrene in a suitable solvent such asdichloromethane. Process (n) may also involve activation of a carboxylicacid with a suitable coupling agent such as dicyclohexylcarbodiimidefollowed by reaction with the compound of formula (XV).

In process (o), examples of protecting groups and the means for theirremoval can be found in T. W. Greene ‘Protective Groups in OrganicSynthesis’ (J. Wiley and Sons, 1991). Suitable amine protecting groupsinclude sulphonyl (e.g. tosyl), acyl (e.g. acetyl,2′,2′,2′-trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl)and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g.using an acid such as hydrochloric acid) or reductively (e.g.hydrogenolysis of a benzyl group or reductive removal of a2′,2′,2′-trichloroethoxycarbonyl group using zinc in acetic acid) asappropriate. Other suitable amine protecting groups includetrifluoroacetyl (—COCF₃) which may be removed by base catalysedhydrolysis or a solid phase resin bound benzyl group, such as aMerrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), whichmay be removed by acid catalysed hydrolysis, for example withtrifluoroacetic acid.

Process (p) may be performed using conventional interconversionprocedures such as epimerisation, oxidation, reduction, alkylation,nucleophilic or electrophilic aromatic substitution, ester hydrolysis oramide bond formation.

Compounds of formula (II) wherein R³ represents —(CH₂)_(q)—NR¹¹R¹² maybe prepared in accordance with the following procedure:

wherein R², n, q, R¹¹ and R¹² are as defined above, P¹ represents aprotecting group such as methyl, ethyl or t-butyl, L¹⁰ and L¹¹independently represent a leaving group such as halogen (eg. L¹⁰represents chlorine and L¹¹ represents bromine). The —CO₂H group ofcompounds of formula (II)^(a) may be converted to —COL wherein Lrepresents a leaving group by, for example, halogenation using thionylchloride.

Step (i) typically comprises reaction of a compound of formula (XVI)with a suitable alkylating agent such as 1-bromo-3-chloropropane in asuitable solvent such as acetone in the presence of potassium carbonate.

Step (ii) typically comprises treatment of a compound of formula (XVII)with an amine of formula HNR¹¹R¹².

Step (iii) comprises a deprotection reaction which may be performed forexample under acidic conditions with hydrochloric acid.

Compounds of formula (IV) or (XIV) may be prepared by hydrolysing acompound of formula (XVII) as defined above under suitable conditions(eg. under acidic conditions with HCl), suitably activated (eg. byconversion into the acid chloride with thionyl chloride), followed bytreatment with a compound of formula (III) or (XIII), respectively asdefined above.

Compounds of formula (II) wherein R³ represents —(CH₂)_(q)—NR¹¹R¹² mayalso be prepared in accordance with the following procedure:

wherein R², n, q, R¹¹ and R¹² are as defined above.

Step (i) typically comprises reaction of a compound of formula (XIX) inthe presence of a suitable base such as sodium hydride in an appropriatesolvent such as dimethylsulfoxide or N,N-dimethylformamide.

Step (ii) typically comprises a hydrolysis reaction for example underacidic conditions using hydrochloric acid.

Compounds of formula (IV), (IX), (XI), (XII) and (XIV) may be preparedusing an analogous procedure using HO—(CH₂)_(q)—L¹², wherein q is asdefined above and L¹² represents an OH group or a group convertible to aleaving group.

Compounds of formula (II) wherein R³ represents a group of formula (i)may be prepared in a similar manner to the procedure shown above.

Compounds of formula (V) wherein L² represents chlorine may be preparedin accordance with the following procedure:

wherein R², R³ and n are as defined above.

Step (i) typically comprises reaction of a compound of formula (XXI)with a suitable reagent such as chlorosulfonic acid in a suitablesolvent such as chloroform.

Compounds of formula (VI) may be prepared in accordance with thefollowing procedure:

wherein R², n, q, L³, R^(4b) and R^(5b) are as defined above.

Step (i) may be performed by reacting a compound of formula (XXII) witha suitable reagent such as chlorosulfonic acid in a suitable solventsuch as chloroform.

Step (ii) is typically performed in the presence of a suitable solventsuch as dichloromethane.

Compounds of formula (VII) may be prepared in accordance with thefollowing procedure:

wherein R^(4b), R^(5b), R² and n are as defined above and L¹³ representsa suitable leaving group such as a halogen atom (eg. chlorine).

Step (i) typically comprises reaction of a compound of formula (XXIV)with a compound of formula R^(4b)R^(5b)NH, wherein R^(4b) and R^(5b) areas defined above, in a suitable solvent such as dichloromethane.

Compounds of formula (VIII) are either commercially available or may beprepared via standard routes, for example, imidazolones (e.g.piperidin-4-yl-4-phenyl-1,3-dihydroimidazol-2-one) may be prepared usingthe procedures described by Carling et al., J. Med. Chem., 1999, 42,2706.

Compounds of formula (XV) may be prepared in accordance with thefollowing procedure:

-   -   wherein L, R², n, R³, R⁴′, t and u are as defined above and p²        represents a suitable protecting group such as t-butoxycarbonyl        (t-Boc) or t-butyl.

Compounds of formula H-E^(a), H-E^(b) and H-E^(c) are eithercommercially available or may be prepared via standard routes, forexample, spiro imidazolones (e.g3-benzyl-2-oxo-1,3,8-triazaspiro[4.5]decane) can be prepared asdescribed by Smith et al., J. Med. Chem., 1995, 38, 3772, spiromorpholinones (e.g. 1-oxa-4,9-diazaspiro[5.5]undecan-3-one) may beprepared as described by Clark et al., J. Med. Chem., 1983, 26, 855,spiro oxazolidinones (e.g.3-phenyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one) may be prepared asdescribed by Caroon et al., J. Med. Chem., 1981, 24, 1320.

Compounds of formula R^(4b)R^(5b)NH, (III), (X), (XIII), (XVI), (XIX),(XXI), (XXII), (XXIV) and (XXV) are either known in the literature orcan be prepared by analogous methods.

Compounds of formula (I) and their pharmaceutically acceptable saltshave affinity for and are antagonists and/or inverse agonists of thehistamine H3 receptor and are believed to be of potential use in thetreatment of neurological diseases including Alzheimer's disease,dementia, age-related memory dysfunction, mild cognitive impairment,cognitive deficit, epilepsy, neuropathic pain, inflammatory pain,migraine, Parkinson's disease, multiple sclerosis, stroke and sleepdisorders including narcolepsy; psychiatric disorders includingschizophrenia (particularly cognitive deficit of schizophrenia),attention deficit hypereactivity disorder, depression and addiction; andother diseases including obesity, asthma, allergic rhinitis, nasalcongestion, chronic obstructive pulmonary disease and gastrointestinaldisorders.

Thus the invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof, for use as a therapeuticsubstance in the treatment or prophylaxis of the above disorders, inparticular cognitive impairments in diseases such as Alzheimer's diseaseand related neurodegenerative disorders.

The invention further provides a method of treatment or prophylaxis ofthe above disorders, in mammals including humans, which comprisesadministering to the sufferer a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for use in the treatment of the abovedisorders.

When used in therapy, the compounds of formula (I) are usuallyformulated in a standard pharmaceutical composition. Such compositionscan be prepared using standard procedures.

Thus, the present invention further provides a pharmaceuticalcomposition for use in the treatment of the above disorders whichcomprises the compound of formula (I) or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier.

The present invention further provides a pharmaceutical compositionwhich comprises the compound of formula (I) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.

Compounds of formula (I) may be used in combination with othertherapeutic agents, for example histamine H1 antagonists or medicamentsclaimed to be useful as either disease modifying or symptomatictreatments of Alzheimer's disease. Suitable examples of such othertherapeutic agents may be agents known to modify cholinergictransmission such as 5-HT₆ antagonists, M1 muscarinic agonists, M2muscarinic antagonists or acetylcholinesterase inhibitors. When thecompounds are used in combination with other therapeutic agents, thecompounds may be administered either sequentially or simultaneously byany convenient route.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablederivative thereof together with a further therapeutic agent or agents.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable carrier or excipient comprise a furtheraspect of the invention. The individual components of such combinationsmay be administered either sequentially or simultaneously in separate orcombined pharmaceutical formulations.

When a compound of formula (I) or a pharmaceutically acceptablederivative thereof is used in combination with a second therapeuticagent active against the same disease state the dose of each compoundmay differ from that when the compound is used alone. Appropriate doseswill be readily appreciated by those skilled in the art.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusible solutions or suspensions or suppositories. Orallyadministrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents,fillers, tabletting lubricants, disintegrants and acceptable wettingagents. The tablets may be coated according to methods well known innormal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives,and, if desired, conventional flavourings or colorants.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle. The compound, depending on thevehicle and concentration used, can be either suspended or dissolved inthe vehicle. In preparing solutions, the compound can be dissolved forinjection and filter sterilised before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, preservatives and buffering agents are dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilisation cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspension in a sterilevehicle. Advantageously, a surfactant or wetting agent is included inthe composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration. The dose of the compound used in the treatment of theaforementioned disorders will vary in the usual way with the seriousnessof the disorders, the weight of the sufferer, and other similar factors.However, as a general guide suitable unit doses may be 0.05 to 1000 mg,more suitably 1.0 to 200 mg, and such unit doses may be administeredmore than once a day, for example two or three a day. Such therapy mayextend for a number of weeks or months.

The following Descriptions and Examples illustrate the preparation ofcompounds of the invention.

Description 1

Ethyl 4-(3-Piperidin-1-ylpropoxy)benzoate (D1)

A stirred mixture of ethyl 4-(3-chloropropoxy)benzoate (4.73 g) (D. A.Walsh et al J. Med. Chem. 1989, 32(1), 105), piperidine (2.9 ml), sodiumcarbonate (3.1 g) and potassium iodide (162 mg) in 1-butanol (50 ml) washeated at 105° C. for 16 h. The reaction was cooled to rt, diluted withEtOAc (100 ml), washed with water (3×50 ml), saturated brine (50 ml),dried (MgSO₄) and evaporated to give the title compound (D1) (6.88 g).MS electrospray (+ ion) 292 (MH⁺). ¹H NMR δ (CDCl₃): 7.98 (2H, d, J=8.8Hz), 6.90 (2H, d, J=8.8 Hz), 4.34 (2H, q ,J=7.5 Hz), 4.06 (2H, t, J=6.3Hz), 2.46 (4H, m), 2.00 (2H, m), 1.50 (6H, m), 1.38 (3H, t, J=7.5 Hz).

Description 2

4-(3-Piperidin-1-ylpropoxy)benzoic acid hydrochloride (D2)

A solution of ethyl 4-(3-piperidin-1-ylpropoxy)benzoate (D1) (1.4 g) inconcentrated hydrochloric acid (15 ml) was heated under reflux for 1 h,cooled and evaporated to give the title compound (D2) (1.029). MSelectrospray (+ ion) 264 (MH⁺).¹H NMR δ (DMSO-d6): 10.59 (1H, s), 10.25(1H, s), 7.90 (2H, d, J=9 Hz), 7.02 (2H, d, J=9 Hz), 4.14 (2H, t, J=6Hz), 3.05-3.52 (4H, m), 2.91 (2H, m), 2.20 (2H, m), 1.25-1.91 (6H, m).

Description 3

4-(3-Piperidin-1-ylpropoxy)benzoyl chloride hydrochloride (D3)

4-(3-Piperidin-1-ylpropoxy)benzoic acid hydrochloride (D2) (0.23 g) inthionyl chloride (5 ml) was heated under reflux for 1 h. The reactionmixture was then evaporated to a minimum and coevaporated from DCM (3×10ml) to give the title compound (D3) as a white powder (0.24 g).

Description 4

1-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-4-t-butoxycarbonylpiperazine (D4)

To t-butoxycarbonylpiperazine (5.65 g) in DCM (70 ml) was addedtriethylamine (16.2 ml) followed by slow addition of4-(3-piperidin-1-ylpropoxy)benzoyl chloride hydrochloride (D3) (10.60 g)in DCM (100 ml). The reaction was stirred at rt for 3 h, then washedwith saturated sodium hydrogen carbonate solution (2×200 ml) followed bybrine (100 ml). The organic layer was dried (MgSO₄) and evaporated to abrown solid which was purified by chromatography [silica gel; 0-6% MeOH(containing 10% 0.880 ammonia solution)/DCM] to give the title compound(D4) as a pale brown solid (12.05 g).

Description 5

1-[4-(3-Piperidin-1-ylpropoxy)benzoyl]piperazine Dihydrochloride (D5)

To 1-[4-(3-piperidin-1-ylpropoxy)benzoyl]4-t-butoxycarbonylpiperazine(D4) (12.05 g) in DCM (150 ml) was added 4N HCl/Dioxane (35 ml), forminga white precipitate. The reaction was stirred for 2.5 hours beforeevaporation. The white crude solid was triturated with DCM and driedovernight at 50° C. to yield the title compound (D5) (8.26 g).

Description 6

1-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-4-t-butoxycarbonylhomopiperazine(D6)

Description 6 was prepared in accordance with the procedure describedfor Example 172.

Description 7

1-[4-(3-Piperidin-1-ylpropoxy)benzoyl]homopiperazine dihydrochloride(D7)

To1-[4-(3-piperidin-1-ylpropoxy)benzoyl]4-t-butoxycarbonylhomopiperazine(D6) (1.50 g) in DCM (20 ml) was added 4N HCl (4 ml) and the mixture wasallowed to stir at rt overnight. Evaporation of solvent followed bydrying under high vacuum afforded the title compound (D7) as a whitesolid (1.5 g).

Description 8

(1S,4S)-5-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-2,5-diaza-bicyclo[2.2.1]heptane-2CarboxylicAcid t-Butyl Ester (D8)

Description 8 was prepared in accordance with the procedure describedfor Example 103.

Description 9

(1S,4S)-2-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-2,5-diaza-bicyclo[2.2.1]heptanedihydrochloride (D9)

Description 9 was prepared in accordance with the procedure describedfor Example 104.

Description 10

(3R,5S)-1-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-3,5-dimethylpiperazine(D10)

(2R,6S)-2,6-Dimethyl-piperazine (0.4 g) was dissolved in THF (30 ml) andtreated with n-butyl lithium (1.6M solution in hexanes, 4.82 ml) underargon. The mixture was stirred at rt for 30 min and then4-(3-piperidin-1-ylpropoxy)benzoyl chloride hydrochloride (D3) (1.0 g),dissolved in DCM (10 ml), was added dropwise. The reaction was stirredfor 1 h and then evaporated to a minimum and the crude residue purifiedby column chromatography [silica gel, eluted with 0-10% MeOH (containing10% 0.880 ammonia solution) in DCM] to afford the title compound (D10)as a yellow oil (0.65 g).

Description 11

(S)-N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-3-aminopyrrolidinedihydrochloride (D11)

A solution of 4-(3-piperidin-1-ylpropoxy)benzoic acid hydrochloride (D2)(515 mg) in thionyl chloride (10 ml) was refluxed for 1 h, cooled to rtand evaporated. The acid chloride was re-evaporated from DCM (2×10 ml).The residue was redissolved in DCM (5 ml) and triethylamine (0.67 ml)and added to an ice cold stirred solution of(S)-3-t-butoxycarbonylaminopyrrolidine (304 mg) The solution was allowedto gain rt, stirred for 1 h. and then chromatographed (silica gel, stepgradient 2-6% MeOH in DCM). Fractions containing the required productwere treated with excess hydrogen chloride (4M solution in dioxan) for 2h and then concentrated to yield the title compound (D11) (650 mg). MSelectrospray (+ ion) 332 (MH⁺). ¹H NMR δ (DMSO-d₆), 10.38 (1H, s), 8.40(3H, s), 7.52 (2H, d, J=9 Hz), 6.99 (2H, d, J=9 Hz), 4.11 (2H, t, 6 Hz),2.75-3.92 (11H, m), 2.85 (2H, m), 1.90-2.30 (4H, m), 1.38-1.88 (6H, m).

Description 12

1-Bromo-3-(4-chlorosulfonylphenoxy)propane (D12)

A stirred solution of 3-bromo-1-phenoxypropane (4.3 g) in chloroform (20ml) at −5° C. was treated dropwise with a solution of chlorosulfonicacid (2.66 ml) in chloroform keeping the temperature below 0° C. Thereaction was stirred for 5 min then allowed to gain rt and stirred for 4days. The mixture was poured onto ice and allowed to gain rt. Theorganic layer was collected, washed with water (3×20 ml), saturatedbrine (20 ml), dried (MgSO₄) and evaporated to give the title compound(D12) (1.9 g). ¹H NMR δ (CDCl₃): 7.98 (2H, d, J=8.8 Hz), 7.05 (2H, d,J=8.8 Hz), 4.24 (2H, t, J=5.8 Hz), 3.61 (2H, t, J=5.8 Hz), 2.37 (2H, m).

Description 13

4-[4-(3-Bromopropoxy)benzenesulfonylimorpholine (D13)

A solution of 1-bromo-3-(4-chlorosulfonylphenoxy)propane (D12) (200 mg)in DCM (5 ml) was treated with morpholine (0.14 ml) and stirred for 1 h.The solution was chromatographed (silica, step gradient 15 to 30% EtOAcin light petroleum 40°-60°) to give the title compound (D13) (99 mg). MSelectrospray (+ ion) 365 (MH⁺). ¹H NMR δ (CDCl₃): 7.69 (2H, d, J=9 Hz),7.02 (2H, d, J=9 Hz), 4.19 (2H, t, J=5.8 Hz), 3.74 (4H, m), 3.61 (2H, t,J=5.8 Hz), 2.99 (4H, m), 2.36 (2H, m).

Description 14

4-(3-Piperidin-1-yl-propoxy)-2-trifluoromethyl-benzonitrile (D14)

4-Fluoro-2-trifluoromethyl-benzonitrile (1.20 g) was dissolved in THF(20 ml) and 3-piperidin-1-yl-propan-1-ol (0.91 ml) was added. Thereaction was cooled to 0° C. and potassium hexamethyldisilazide (0.5Msolution in toluene; 12.72 ml) was added dropwise. The reaction wasstirred at rt overnight, then diluted with ethyl acetate (50 ml) andpartitioned with aqueous 1 N HCl (50 ml). The aqueous layer was washedwith ethyl acetate (50 ml), then basified to pH 8.0 with sodium hydrogencarbonate and extracted with ethyl acetate (3×75 ml). The combinedorganic extracts were dried (MgSO₄) and evaporated to give the titlecompound (D14) as a clear oil which crystallised on standing (0.80 g).

Description 15

4-(3-Piperidin-1-yl-propoxy)-2-trifluoromethyl-benzoic acidhydrochloride (D15)

4-(3-Piperidin-1-yl-propoxy)-2-trifluoromethyl-benzonitrile (D14) (0.80g) was dissolved in conc. HCl (20 ml) and heated at 135° C. for 24 h.Concentrated sulfuric acid (10 ml) was added and the reaction heated at135° C. for 36 h. The reaction mixture was then evaporated to a minimumand treated with 12.5 N sodium hydroxide solution until pH 12 wasobtained. The mixture was filtered and the filtrate evaporated to aminimum. Conc. HCl was then added until pH 1. The mixture was evaporatedand the solid residue was extracted several times with methanol. Thecombined extracts were evaporated to give the title compound (D15) as awhite solid (0.90 g).

Description 16

4-(3-Piperidin-1-yl-propoxy)-2-trifluoromethyl-benzoyl chloridehydrochloride (D16)

4-(3-Piperidin-1-yl-propoxy)-2-trifluoromethyl-benzoic acidhydrochloride (D15) (0.9 g) was heated at reflux in thionyl chloride (20ml) for 2 h. The reaction mixture was evaporated to a minimum thenco-evaporated with DCM (3×) to give the title compound (D16) as a whitesolid (1.0 g)

Description 17

2,5-Difluoro-4-(3-piperidin-1-yl)propoxy)benzonitrile (D17)

The title compound was prepared using the method of Description 14 from2,4,5-trifluorobenzonitrile.

Description 18

2,5-Difluoro-4-(3-piperidin-1-ylpropoxy)benzoic Acid Hydrochloride (D18)

2,5-Difluoro-4-(3-piperidin-1-ylpropoxy)benzonitrile (D17) (1.1 g) wasdissolved in conc.

HCl and heated under reflux for 24 h. The reaction mixture was thencooled to 5° C. and the resultant precipitate filtered and dried at 50°C. under high vacuum to give the title compound (D18) (0.56 g).

Description 19

2,5-Difluoro-4-(3-piperidin-1-ylpropoxy)benzoyl chloride hydrochloride(D19)

The title compound was prepared from2,5-difluoro-4-(3-piperidin-1-yl)propoxy)benzoic acid hydrochloride(D18) using the method of Description 16.

Description 20

2-Fluoro-4-(3-piperidin-1-ylpropoxy)benzonitrile (D20)

The title compound was prepared using the method of Description 14 from2,4-difluorobenzonitrile.

Description 21

2-Fluoro-4-(3-piperidin-1-ylpropoxy)benzoic acid hydrochloride (D21)

2-Fluoro-4-(3-piperidin-1-ylpropoxy)benzonitrile (D20) (1.4 g) wasdissolved conc. HCl and heated under reflux for 24 h. The reactionmixture was then cooled to 5° C. and the resultant precipitate filteredand dried at 50° C. under high vacuum to give the title compound (D21)(1.5 g).

Description 22

2-Fluoro-4-(3-piperidin-1-ylpropoxy)benzoyl chloride hydrochloride (D22)

The title compound was prepared from2-fluoro-4-(3-piperidin-1-ylpropoxy) benzoic acid hydrochloride (D21)using the method of Description 16.

Description 23

1-tert-Butoxycarbonyl-4-[4-fluoro-2-trifluoromethyl-benzoyl]piperazine(D23)

4-Fluoro-2-(trifluoromethyl)benzoic acid (2.0 g) was dissolved inthionyl chloride (20 ml) and heated at reflux for 2 h. The reaction wasthen cooled and evaporated (co-evaporated with DCM×3) and then dissolvedin DCM (50 ml). This solution was added slowly to1-tert-butoxy-carbonylpiperazine (1.62 g), and TEA (2.54 ml), dissolvedin DCM (50 ml). The reaction was then stirred at rt for 2 h before beingwashed with 1 N HCl (2×100 ml), saturated sodium hydrogen carbonate(2×100 ml) and brine (50 ml). The organic layer was dried (MgSO₄) andevaporated to give the title compound (D23) (3.09 g).

Description 24

1-tert-Butoxycarbonyl-4-[4-(3-piperidin-1-ylpropoxy)-2-trifluoromethyl-benzoyl]piperazine(D24)

1-tert-Butoxycarbonyl-4-[4-fluoro-2-trifluoromethyl-benzoyl]piperazine(D23) (2.05 g) and 3-(1-piperidinyl)-1-propanol (1.17 g) were dissolvedin DMSO (30 ml) and KHMDS (12.2 ml, 20% in THF) was added slowly and thereaction was stirred for 30 min. The reaction mixture was thenevaporated and re-dissolved in ethyl acetate and washed with saturatedsodium hydrogen carbonate (2×80 ml) and brine (80 ml). The organic layerwas dried (MgSO₄) and evaporated, and the residue purified bychromatography [silica gel; gradient elution with 0-10% MeOH (containing10% 0.880 ammonia solution)/DCM].

Pure product fractions were evaporated and dried under high vacuum togive the title compound (D24) as a white solid (2.15 g).

Description 25

1-[4-(3-piperidin-1-ylpropoxy)-2-trifluoromethyl-benzoyl]piperazinedihydrochloride (D25)

1-tert-Butoxycarbonyl-4-[4-(3-piperidin-1-ylpropoxy)-2-trifluoromethyl-benzoyl]piperazine(D24) (2.15 g) was dissolved in DCM (50 ml) and 4N HCl in dioxane (25ml) was added and the reaction stirred at rt overnight. The reactionmixture was then evaporated [co evaporated with toluene (3×), thenacetone (3×)] to give the title compound (D25) as a white foam (1.82 g).

Description 26

(3R,5S)-1-tert-Butoxycarbonyl-3,5-dimethyl-4-(4-fluorobenzoyl)piperazinedihydrochloride (D26)

(2R,6S)-2,6-Dimethylpiperazine (0.9 g) was stirred in THF (50 ml) andn-butyl lithium (2.5M in hexanes) (6.9 ml) was added. The mixture wasstirred for 30 min and then TMSCI (1.1 ml) was added. The reaction wasstirred for a further 30 min and then 4-fluorobenzoyl chloride (1.0 g)in THF (5 ml) was added dropwise and the reaction stirred for a further30 min. Methanol (10 ml) was then added and the reaction evaporated todryness. The crude amine intermediate was dissolved in DCM (30 ml) andTEA (1.23 ml) was added followed by di-tert-butyl dicarbonate (1.7 g)and the reaction stirred at rt under argon overnight. The mixture wasthen washed with saturated sodium hydrogen carbonate (3×50 ml) and brine(50 ml), dried (MgSO₄) and evaporated to yield the crude product whichwas purified by column chromatography [silica gel; gradient elution;0-100% EtOAc:Hexane]. Fractions containing pure product were evaporatedto give the title compound (D26) (0.67 g).

Description 27

(3R,5S)-1-tert-Butoxycarbonyl-3,5-dimethyl-4-[4-(3-piperidin-1-yl)propoxybenzoyl]piperazinedihydrochloride (D27)

(3R,5S)1-tert-Butoxycarbonyl-3,5-dimethyl-4-(4-fluorobenzoyl)piperazinedihydrochloride (D26) (0.56 g) was dissolved in DMSO (5 ml) and3-(1-piperidinyl)-1-propanol (0.249) was added followed by dropwiseaddition of KHMDS (0.5 M in toluene) (3.3 ml), and the reaction wasstirred at rt under argon for 2 h. The reaction mixture was thenevaporated and redissolved in ethyl acetate (100 ml), washed withsaturated sodium hydrogen carbonate (3×50 ml), brine (50 ml) and dried(MgSO₄) before being evaporated. The crude product was chromatographed[silica gel, gradient elution, 0-10% MeOH (containing 10% 0.880 ammoniasolution)/DCM]. Pure product fractions were evaporated to give the titlecompound (D27) as a clear oil (0.2 g).

Description 28

(2R,6S)-2,6-Dimethyl-1-[4-(3-piperidin-1-yl)propoxybenzoyl]piperazinedihydrochloride (D28)

(3R,5S)-1-tert-Butoxycarbonyl-3,5-dimethyl-4-[4-(3-piperidin-1-yl)propoxybenzoyl]piperazinedihydrochloride (D27) (0.2 g) was dissolved in DCM (5 ml) and 4NHCl/dioxane (5 ml) was added and the reaction stirred for 16 h. Thereaction mixture was then evaporated (co-evaporated with toluene 3×) togive the title compound (D28) as a white powder (0.18 g).

Description 29

4-[(1-tert-Butoxycarbonyl-4-piperidinyl)oxy]benzonitrile (D29)

4-Fluorobenzonitrile (3.0 g) was dissolved in THF (50 ml) and thenN-tert-butoxy-carbonyl-4-piperidinol (4.98 g) was added. Potassiumhexamethyldisilazide (20% wt solution in THF, 24.62 g) was then addeddropwise and the reaction stirred at rt for 2 h. The reaction mixturewas then evaporated to a minimum, redissolved in EtOAc (100 ml) andwashed with aqueous 1N HCl (2×100 ml), saturated sodium bicarbonatesolution (2×100 ml) and brine (100 ml). The organic layer was dried(MgSO₄) and then purified by chromatography [silica gel, step gradient0-60% EtOAc/Hexane]. Fractions containing the required product wereevaporated to give the title compound (D29) as a clear oil whichcrystallised on standing (6.83 g). ¹H NMR δ (CDCl₃): 7.59 (2H, d, J=7.50Hz), 6.95 (2H, d, J=7.50 Hz), 4.44 (1H, m), 3.70 (2H, m), 3.38 (2H, m),1.91 (2H, m), 1.77 (2H, m), 1.47 (9H, s).

Description 30

4-(4-Piperidinyloxy)benzonitrile trifluoroacetate (D30)

4-[(1-tert-Butoxycarbonyl-4-piperidinyl)oxy]benzonitrile (D29) (6.83 g)was dissolved in DCM (30 ml) and TFA (30 ml) was added. The reaction wasstirred at rt for 1 h and then evaporated to give the title compound(D30) as a yellow oil (7.15 g—TFA salt plus 1.3 equivalents of TFA).

Description 31

4-[(1-Cyclobutyl-4-piperidinyl)oxy]benzonitrile (D31)

4-(4-Piperidinyloxy)benzonitrile trifluoroacetate (D30) (2.2 g) wasdissolved in DCM (50 ml) and triethylamine (1.92 ml) was added followedby cyclobutanone (0.649). The mixture was stirred for 5 min, then sodiumtriacetoxyborohydride (1.94 g) was added and the reaction was stirred atrt under argon overnight. The reaction mixture was then washed withsaturated potassium carbonate solution (3×30 ml) and brine (30 ml). Theorganic layer was dried (MgSO₄) and evaporated to give the titlecompound (D31) as a white solid (1.91 g). ¹H NMR δ (CDCl₃): 7.56 (2H, d,J=6.84 Hz), 6.93 (2H, d, J=6.80 Hz), 4.41 (1H, m), 2.77 (1H, m), 2.75(2H, m), 2.30 (2H, m), 2.06 (4H, m), 1.87 (4H, m), 1.66 (2H, m).

Description 32

4-[(1-Isopropyl-4-piperidinyl)oxy]benzonitrile (D32)

The title compound was prepared in a similar manner to Description 31using acetone in place of cyclobutanone.

Description 33

4-[(1-Cyclopentyl-4-piperidinyl)oxy]benzonitrile (D33)

The title compound was prepared in a similar manner to Description 31using cyclopentanone in place of cyclobutanone.

Description 34

4-[(1-Cyclobutyl-4-piperidinyl)oxy]benzoic Acid Hydrochloride (D34)

4-[(1-Cyclobutyl-4-piperidinyl)oxy]benzonitrile (D31) (1.91 g) wasdissolved in conc. HCl (30 ml) and heated to 120° C. for 2 h. Thereaction mixture was then allowed to cool to rt and then further cooledto 5° C. The resultant white precipitate was filtered off and washedwith a small quantity of water. The solid was then dried at 50° C. undervacuum overnight to yield the title compound (D34) as a white powder(0.95 g). ¹H NMR δ (DMSO-d₆): 12.60 (1H, s), 10.96 (1H, s), 7.90 (2H, d,J=8.70 Hz), 7.09 (2H, d, J=8.60 Hz), 4.09-4.64 (1H, m), 3.66-3.15 (3H,m), 2.99-2.77 (2H, m), 2.48-1.60 (10H, m).

Description 35

4-[(1-Cyclobutyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride (D35)

4-[(1-Cyclobutyl-4-piperidinyl)oxy]benzoic acid hydrochloride (D34)(0.20 g) was dissolved in thionyl chloride (10 ml) and heated underreflux for 1.5 h. The thionyl chloride was removed by evaporation andthe residue evaporated from DCM (3×10 ml) to give the title compound(D35) (0.21 g).

Description 36

4-[(1-Cyclobutyl-4-piperidinyl)oxy]benzoyl]4-t-butoxycarbonylpiperazine(D36)

To t-butoxycarbonylpiperazine (0.62 g) in DCM (50 ml) was addedtriethylamine (1.3 ml) followed by slow addition of4-[(1-cyclobutylpiperidinyl)oxy]benzoyl chloride hydrochloride (D35)(1.16 g) in DCM (50 ml). The reaction was stirred at rt for 16 h, thenwashed with saturated sodium hydrogen carbonate solution (3×50 ml)followed by brine (50 ml). The organic layer was dried (MgSO₄) andevaporated to a brown solid which was purified by chromatography [silicagel; step gradient 0-10% MeOH (containing 10% 0.880 ammoniasolution)/DCM] to give the title compound (D36) as a pale brown solid(1.0 g).

Description 37

4-[(1-Cyclobutyl-4-piperidinyl)oxy]benzoyl]piperazine dihydrochloride(D37)

To4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl]-4-t-butoxycarbonylpiperazine(D36) (1.0 g) in DCM (30 ml) was added 1N HCl in diethyl ether (30 ml),forming a white precipitate. The reaction was stirred for 16 h beforeevaporation. The white crude solid was dried overnight at 50° C. toyield the title compound (D37) (0.87 g).

Description 38

4-[(1-Isopropyl-4-piperidinyl)oxy]benzoyl]piperazine dihydrochloride(D38)

The title compound was prepared from4-[(1-isopropyl-4-piperidinyl)oxy]benzonitrile (D32) following theprocedures in Descriptions 34-37.

Description 39

4-[(1-Cyclopentyl-4-piperidinyl)oxy]benzoyl]piperazine dihydrochloride(D39)

The title compound was prepared from4-[(1-cyclopentyl-4-piperidinyl)oxy]benzonitrile (D33) following theprocedures in Descriptions 34-37.

EXAMPLE 1 N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-4-phenylpiperazinedihydrochloride (E1)

A solution of 4-(3-piperidin-1-ylpropoxy)benzoic acid hydrochloride (D2)(500 mg) in thionyl chloride (5 ml) was refluxed for 1 h, cooled to rtand evaporated. The acid chloride was re-evaporated from DCM (2×10 ml).The residue was redissolved in DCM (5 ml) and triethylamine (0.7 ml) andadded to a stirred solution of 4-phenylpiperazine (270 mg) in DCM (20ml) at rt. The mixture was stirred for 1 h, washed with saturated sodiumhydrogen carbonate solution (10 ml), water (3×10 ml), dried (MgSO₄) andevaporated. The residue was chromatographed (silica gel, step gradient2-6% MeOH in DCM). Fractions containing the required product weretreated with excess hydrogen chloride (4M solution in dioxan) and thenconcentrated to yield the title compound (E1) (630 mg). MS electrospray(+ ion) 408 (MH⁺).¹H NMR δ (DMSO-d₆): 10.39 (1H,s), 6.90-7.47 (9H, m),4.11 (2H, t, J=6 Hz), 2.66-3.89 (12H, m), 2.24 (2H, m), 1.22-1.83 (6H,m).

EXAMPLE 2 N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]piperazinedihydrochloride (E2)

4-(3-Piperidin-1-ylpropoxy)benzoic acid hydrochloride (D2) (150 mg) wasconverted to the title compound (E2) by reaction with4-t-butoxycarbonylpiperazine (93 mg) using the method described inExample 1 (E1) except that the treatment with excess hydrogen chloride(4M solution in dioxan) was continued for 2 h before evaporation(yield=125 mg). MS electrospray (+ ion) 332 (MH⁺).¹H NMR δ (DMSO-d6),10.51 (1H, s), 9.50 (1H, s), 7.44 (2H, d, J=8.8 Hz), 7.00 (2H, d, J=8.8Hz), 4.11 (2H, t, J=6 Hz), 3.71 (4H, m), 3.35 (8H, m), 2.87 (2H, m),2.22 (2H, m), 1.30-1.90 (6H, m).

EXAMPLES 3-5 E3-5

Examples 3-5 were prepared from 4-(3-piperidin-1-ylpropoxy)benzoic acidhydrochloride (D2) and the appropriate amine using the method outlinedin Example 1 (E1) and displayed ¹H NMR and mass spectral data that wereconsistent with structure.

Mass Spectrum Example No R^(x) (ES⁺) E3

374 [M + H]⁺ E4

432 [M + H]⁺ E5

346 [M + H]⁺

EXAMPLES 6-13 E6-13

Examples 6-13 were prepared from 4-(3-piperidin-1-ylpropoxy)benzoic acidhydrochloride (D2) and the appropriate amine using the method outlinedin Example 1 (E1) with the exception that polymer supported base wasemployed. All compounds displayed ¹H NMR and mass spectral data thatwere consistent with structure.

Exam- ple No R^(x) Mass Spectrum E6

477 [M + H]⁺ E7

426 [M + H]⁺ E8

442, 444 [M + H]⁺ E9

442, 444 [M + H]⁺ E10

410 [M + H]⁺ E11

409 [M + H]⁺ E12

422 [M + H]⁺ E13

438 [M + H]⁺

EXAMPLES 14-51 E14-51

Examples 14-51 were prepared from 4-(3-piperidin-1-ylpropoxy)benzoicacid hydrochloride (D2) and the appropriate amine using the methodoutlined in Example 1 (E1) with the exception thatdiethylaminomethylpolystyrene was employed as the base. All compoundsdisplayed ¹H NMR and mass spectral data that were consistent withstructure.

Exam- ple No R^(x) Mass Spectrum E14

433 [M + H]⁺ E15

410 [M + H]⁺ E16

410 [M + H]⁺ E17

426 [M + H]⁺ E18

500/502 [M + H]⁺ E19

346 [M + H]⁺ E20

457 [M + H]⁺ E21

511/513 [M + H]⁺ E22

434 [M + H]⁺ E23

425 [M + H]⁺ E24

438 [M + H]⁺ E25

473 [M + H]⁺ E26

417 [M + H]⁺ E27

436 [M + H]⁺ E28

455/457 [M + H]⁺ E29

498 [M + H]⁺ E30

448 [M + H]⁺ E31

446 [M + H]⁺ E32

416 [M + H]⁺ E33

422 [M + H]⁺ E34

477 [M + H]⁺ E35

436 [M + H]⁺ E36

477/479/481 [M + H]⁺ E37

476 [M + H]⁺ E38

410 [M + H]⁺ E39

409 [M + H]⁺ E40

450 [M + H]⁺ E41

428 [M + H]⁺ E42

436 [M + H]⁺ E43

423 [M + H]⁺ E44

492 [M + H]⁺ E45

479 [M + H]⁺ E46

443 [M + H]⁺ E47

476 [M + H]⁺ E48

478 [M + H]⁺ E49

477 [M + H]⁺ E50

436 [M + H]⁺ E51

360 [M + H]⁺

EXAMPLES 52-54 E52-E54

Examples 52-54 (E52-E54) were prepared from4-(3-piperidin-1-yl-propoxy)-2-trifluoromethyl-benzoyl chloride (D16)and the appropriate aryl piperazine according to the method described inExample 1 except that diethylaminomethyl polystyrene was employed as thebase. The final products were purified by chromatography, and convertedto the corresponding HCl salts with 1 M HCl in diethyl ether. Allcompounds displayed ¹H NMR and mass spectral data that were consistentwith structure.

Example Mass No R^(x) Spectrum E52

477 [M + H]⁺ E53

502 [M + H]⁺ E54

476 [M + H]⁺

EXAMPLE 55N-[2,5-Difluoro-4-(3-piperidin-1-ylpropoxy)benzoyl]-4-phenylpiperazinedihydrochloride (E55)

The title compound was prepared from2,5-difluoro-4-(3-piperidin-1-ylpropoxy)benzoyl chloride hydrochloride(D19) and 4-phenylpiperazine according to the method described inExample 1 except that diethylaminomethyl polystyrene was employed as thebase.

MS electrospray (+ ion) 444 (MH⁺).

EXAMPLE 56N-[2-Fluoro-4-(3-Piperidin-1-ylpropoxy)benzoyl]-4-phenylpiperazinedihydrochloride (E56)

The title compound was prepared from2-fluoro-4-(3-piperidin-1-ylpropoxy)benzoyl chloride hydrochloride (D22)and 4-phenylpiperazine according to the method described in Example 1except that diethylaminomethyl polystyrene was employed as the base.

MS electrospray (+ ion) 426 (MH⁺).

EXAMPLE 571-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-4-(1-cyclohexanecarbonyl)-piperazinehydrochloride (E57)

To 4-(3-piperidin-1-ylpropoxy)benzoyl chloride hydrochloride (D3) (0.24g) in DCM (10 ml) was added 1-(cyclohexanecarbonyl)-piperazine (0.155 g)and diethylaminomethyl polystyrene (3.2 mmol/g, 0.699). The mixture wasstirred for 16 h. The reaction mixture was then loaded directly onto asilica column and eluted with 0-10% MeOH (containing 10% 0.880 ammoniasolution) in DCM. The isolated free base was dissolved in DCM (5 ml) andtreated with 4N HCl/Dioxane solution (1 ml) with stirring for 10 min.The reaction was concentrated, and the residue co-evaporated withtoluene (3×10 ml) and then dried at 50° C. under high vacuum for 16 h toyield the title compound (E57) as a pale solid (0.165 g). MSelectrospray (+ ion)-442 (MH⁺).¹H NMR δ (DMSO-d₆): 9.71 (s, 1H), 7.39(d, 2H, J=6.84 Hz), 7.00 (d, 2H, J=6.84 Hz), 4.10 (m, 2H), 3.47-3.25 (m,10H), 3.16 (m, 2H), 2.90 (m, 2H), 2.55 (m, 1H), 2.19 (m, 2H), 1.82-1.62(m, 10H), 1.40-1.16 (m, 6H).

EXAMPLE 581-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-4-(2-furoyl)-piperazinehydrochloride (E58)

The title compound was prepared from 4-(3-piperidin-1-ylpropoxy)benzoylchloride hydrochloride (D3) (0.24 g) and 1-(2-furoyl)piperazine (0.12 g)using the procedure described for Example 1 and isolated as a paleyellow solid (0.16 g). MS electrospray (+ ion) 426 (MH⁺).¹H NMR δ(DMSO-d₆): 9.80 (s, 1H), 7.84 (s, 1H), 7.43 (d, 2H, J=6.80 Hz), 7.03 (m,1H), 7.02 (d, 2H, J=6.80 Hz), 6.63 (m, ₁H), 4.11 (m, 1H), 3.72-3.45 (m,10H), 3.16 (m, 2H), 2.90 (m, 2H), 2.18 (m, 2H), 1.82-1.40 (m, 6H).

EXAMPLE 591-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-4-(thiophen-2-carbonyl)-piperazineHydrochloride (E59)

1-[4-(3-Piperidin-1-ylpropoxy)benzoyl]piperazine dihydrochloride (D5)(0.15 g) was stirred with diethylaminomethyl polystyrene (3.2 mmol/g,0.35 g) in DCM (10 ml) and thiophen-2-carbonyl chloride (0.057 g) wasadded. The reaction was stirred for 16 h and then loaded directly onto asilica column, eluting with 0-10% MeOH (containing 10% 0.880 ammoniasolution)/DCM. The isolated free base product was then dissolved in DCM(5 ml) and treated with 4N HCl/Dioxane solution (1 ml) and stirred for10 min. The reaction was concentrated, and the residue co-evaporatedwith toluene (3×10 ml) then dried at 50° C. under high vacuum for 16 hto yield the title compound (E59) as a pale yellow solid (0.14 g). MSelectrospray (+ ion) 442 (MH⁺). ¹H NMR δ (DMSO-6): 9.85 (s, 1H), 7.77(m, 1H), 7.44 (m, 3H), 7.13 (m, 1H), 7.01 (d, 2H, 8.72 Hz), 4.10 (m,2H), 3.70-3.34 (m, 10H), 3.17 (m, 1H), 2.89 (m, 2H), 2.17 (m, 2H),1.79-1.37 (m, 6H).

EXAMPLES 60-74 E60-E74

Examples 60-74 were prepared from1-[4-(3-piperidin-1-ylpropoxy)benzoyl]piperazine dihydrochloride (D5)and the appropriate acid chloride using the procedure described inExample 59 and displayed ¹H NMR and mass spectral data that wereconsistent with structure.

Example Mass Spectrum No R^(x) (ES⁺) E60

[M + H]⁺ 461 E61

[M + H]⁺ 461 E62

[M + H]⁺ 600 E63

[M + H]⁺ 437 E64

[M + H]⁺ 505 E65

[M + H]⁺ 488 E66

[M + H]⁺ 452 E67

[M + H]⁺ 494 E68

[M + H]⁺ 555 E69

[M + H]⁺ 455 E70

[M + H]⁺ 427 E71

[M + H]⁺ 496 E72

[M + H]⁺ 454 E73

[M + H]⁺ 496 E74

[M + H]⁺ 496

EXAMPLES 75-77 E75-E77

Examples 75-77 were prepared from1-[4-(3-piperidin-1-ylpropoxy)benzoyl]homopiperazine dihydrochloride(D7) and the appropriate carboxylic acid chloride or carbamoyl chloridefollowing the procedure described for Example 59 and displayed ¹H NMRand mass spectral data that were consistent with structure.

Example Mass Spectrum No R^(x) (ES⁺) E75

[M + H]⁺ 475 E76

[M + H]⁺ 475 E77

[M + H]⁺ 459

EXAMPLES 78 AND 79 E78-E79

Examples 78 and 79 were prepared from(1S,4S)-2-[4-(3-piperidin-1-ylpropoxy)benzoyl]-2,5-diaza-bicyclo[2.2.1]heptanedihydrochloride (D9) and the appropriate acid chloride following theprocedure described for Example 59 and displayed ¹H NMR and massspectral data that were consistent with structure.

Example Mass Spectrum No R^(x) (ES⁺) E78

[M + H]⁺ 483 E79

[M + H]⁺ 473

EXAMPLES 80 AND 81 E80-E81

Examples 80 and 81 were prepared from(1S,4S)-2-[4-(3-piperidin-1-ylpropoxy)benzoyl]-2,5-diaza-bicyclo[2.2.1]heptanedihydrochloride (D9) and the appropriate carbamoyl chloride followingthe procedure described for Example 59, and displayed ¹H NMR and massspectral data that were consistent with structure.

Example Mass Spectrum No R^(x) (ES⁺) E80

[M + H]⁺ 441 E81

[M + H]⁺ 457

EXAMPLES 82-87 E82-E87

Examples 82-87 were prepared from1-[4-(3-piperidin-1-ylpropoxy)benzoyl]piperazine dihydrochloride (D5)and the appropriate carboxylic acid chloride using the proceduredescribed in Example 59 and displayed ¹H NMR and mass spectral data thatwere consistent with structure.

Example Mass Spectrum No R^(x) (ES⁺) E82

[M + H]⁺ 402 E83

[M + H]⁺ 436 E84

[M + H]⁺ 471 E85

[M + H]⁺ 471 E86

[M + H]⁺ 504 E87

[M + H]⁺ 504

EXAMPLE 881-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-4-(pyrrolidine-1-carbonyl)-piperazineHydrochloride (E88)

The title compound (E88) was prepared from1-[4-(3-piperidin-1-ylpropoxy)benzoyl]piperazine dihydrochloride) (D5)(0.15 g) and pyrrolidine-1-carbonyl chloride (0.054 g) using theprocedure described in Example 59 and was obtained as a white solid(0.10 g). MS electrospray (+ ion) 429 (MH⁺). ¹H NMR δ (DMSO-d₆): 9.75(s, 1H), 7.40 (d, 2H, J=8.4 Hz), 7.00 (d, 2H, J=8.4 Hz), 4.10 (t, 2H,J=6.0 Hz), 3.47 (m, 6H), 3.27 (m, 4H), 3.18 (m, 6H), 2.87 (m, 2H), 2.17(m, 2H), 1.74-1.39 (m, 10H).

EXAMPLE 891-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-4-(cycloheptanecarbonyl)-piperazineHydrochloride (E89)

1-[4-(3-Piperidin-1-ylpropoxy)benzoyl]piperazine dihydrochloride (D5)(0.15 g) was dissolved in DCM (5 ml) and diethylaminomethyl polystyreneresin (3.2 mmol/g, 0.465 g) was added, followed by cycloheptanecarboxylic acid (0.063 g), HOBT (0.065 g), and EDC (0.092 g). Thereaction was stirred at rt overnight, then filtered and washed withsaturated sodium hydrogen carbonate solution (3×50 ml) and brine (50ml). The organic layer was dried (magnesium sulphate) and evaporated togive a crude product, which was purified by column chromatography[silica gel, eluted with 0-10% MeOH (containing 10% 0.880 ammoniasolution) in DCM]. The isolated free base was then dissolved in DCM (5ml) and treated with 4N HCl/dioxane solution (1 ml) and stirred for 10min. The reaction was concentrated, and the residue co-evaporated withtoluene (3×10 ml) then dried at 50° C. under high vacuum for 16 h toyield the title compound (E89) as a pale solid (0.051 g). MSelectrospray (+ ion) 456 (MH⁺).¹H NMR δ (DMSO-d₆): 9.55 (s, 1H), 7.40(d, 2H, J=8.76 Hz), 7.00 (d, 2H, J=8.76 Hz), 4.10 (t, 2H, J=9.93 Hz),3.51 (m, 10H), 3.17 (m, 2H), 2.90 (m, 2H), 2.73 (m, 1H), 2.18 (m, 2H),1.83-1.66 (m, 9H), 1.44 (m, 9H).

EXAMPLES 90-99 E90-E99

Examples 90-99 were prepared from1-[4-(3-piperidin-1-ylpropoxy)benzoyl]piperazine dihydrochloride (D5)and the appropriate carboxylic acid using the procedure described inExample 89 and displayed ¹H NMR and mass spectral data that wereconsistent with structure.

Example Mass Spectrum No R^(x) (ES⁺) E90

[M + H]⁺ 437 E91

[M + H]⁺ 451 E92

[M + H]⁺ 452 E93

[M + H]⁺ 456 E94

[M + H]⁺ 498 E95

[M + H]⁺ 430 E96

[M + H]⁺ 444 E97

[M + H]⁺ 464 E98

[M + H]⁺ 490 E99

[M + H]⁺ 478

EXAMPLE 100(3R,5S)-1-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-3,5-dimethyl-4-benzoyl-piperazine]hydrochloride(E100)

(3R,5S)-1-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-3,5-dimethylpiperazine(D10) (0.15 g) was dissolved in DCM (5 ml) and treated withdiethylaminomethyl polystyrene resin (3.2 mmol/g, 0.60 g) followed bybenzoyl chloride (0.053 g). The reaction was stirred at rt for 16 h andthen loaded directly onto a silica column, eluting with 0-10% MeOH(containing 10% 0.880 ammonia solution)/DCM. The isolated free baseproduct was then dissolved in DCM (5 ml) and treated with 4N HCl/Dioxanesolution (1 ml) and stirred for 10 min. The reaction was concentrated,and the residue co-evaporated with toluene (3×10 ml) then dried at 50°C. under high vacuum for 16 h to yield the title compound (E100) as awhite solid (0.90 g). MS electrospray (+ ion) 464 (MH⁺).¹H NMR δ(DMSO-d6): 9.74 (1H, s), 7.39 (7H, m), 7.01 (2H, d, J=8.7 Hz), 4.40-4.09(4H, m) 3.47-3.15 (6H, m), 2.92 (2H, m), 2.20-1.28 (10H, m), 1.15 (6H,m).

EXAMPLES 101-102 E101-E102

Examples 101-102 were prepared from(3R,5S)-1-[4-(3-piperidin-1-ylpropoxy)benzoyl]-3,5-dimethylpiperazine(D10) and the appropriate carboxylic acid chloride using the proceduredescribed in Example 100 and displayed ¹H NMR and mass spectral datathat were consistent with structure.

Example Mass Spectrum No R^(X) (ES⁺) E101

[M + H]⁺ 454 E102

[M + H]⁺ 470

EXAMPLE 103(1S,4S)-5-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-2,5-diaza-bicyclo[2.2.1]heptane-2Carboxylic Acid t-Butyl Ester (E103)

To (1S,4S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid t-butylester (1.12 g) in DCM (10 ml) was added triethylamine (1.77 ml) and thereaction was cooled to 0° C. followed by the slow addition of4-(3-piperidin-1-ylpropoxy)benzoyl chloride hydrochloride (D3) (1.8 g)in DCM (10 ml). The mixture was stirred at rt for 3 h, then washed withwater. The organic layer was dried (MgSO₄) and evaporated to give thetitle compound (E103) as a cream coloured solid (2.52 g).

Mass Spectrum 444 [M+H]+

EXAMPLE 104(1S,4S)-2-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-2,5-diaza-bicyclo[2.2.1heptane dihydrochloride (E104)

To(1S,4S)-5-[4-(3-piperidin-1-ylpropoxy)benzoyl]-2,5-diaza-bicyclo[2.2.1]heptane-2carboxylic acid tert-butyl ester (E103) (2.52 g) in DCM (30 ml) wasadded 4N HCl (5 ml) and the mixture was allowed to stir at rt overnight.Evaporation of solvent followed by drying under high vacuum afforded thetitle compound (E104) as a foam (1.2 g).

EXAMPLES 105-114 E105-E114

Examples 105-114 were prepared from1-[4-(3-piperidin-1-ylpropoxy)benzoyl]piperazine dihydrochloride (D5)and the appropriate acid using a similar procedure to that described inExample 89 and employing either DCM or DMF as solvent. All compoundsdisplayed ¹H NMR and mass spectral data that were consistent withstructure.

Example Mass Spectrum No R^(X) (ES⁺) E105

[M + H]⁺ 338 E106

[M + H]⁺ 430 E107

[M + H]⁺ 476 E108

[M + H]⁺ 494 E109

[M + H]⁺ 426 E110

[M + H]⁺ 454 E111

[M + H]⁺ 496 E112

[M + H]⁺ 511/513 E113

[M + H]⁺ 490 E114

[M + H]⁺ 445

EXAMPLES 115-122 E115-E122

Examples 115-122 were prepared using either Method A or B according tothe table, and displayed ¹H NMR and mass spectral data that wereconsistent with structure.

Method A

1-[4-(3-Piperidin-1-ylpropoxy)-2-trifluoromethyl-benzoyl]piperazinedihydrochloride (D25) was reacted with the appropriate acid chloridefollowing the method of Example 100 (E100). The isolated free base wasconverted into the hydrochloride salt and crystallised from acetone.

Method B

1-[4-(3-Piperidin-1-ylpropoxy)-2-trifluoromethyl-benzoyl]piperazinedihydrochloride (D25) was reacted with the appropriate carboxylic acidfollowing the method of Example 89 (E89) except that DMF was employed assolvent. The isolated free base was converted into the hydrochloridesalt and crystallised from acetone.

Example Mass Spectrum Synthetic No R^(X) (ES⁺) Method E115

[M + H]⁺ 494 A E116

[M + H]⁺ 510 A E117

[M + H]⁺ 539 A E118

[M + H]⁺ 497 A E119

[M + H]⁺ 562 B E120

[M + H]⁺ 573 B E121

[M + H]⁺ 498 B E122

[M + H]⁺ 512 B

EXAMPLES 123 AND 124 E123-E124

Examples 123 and 124 were prepared from(2R,6S)-2,6-dimethyl-1-[4-(3-piperidin-1-yl)propoxybenzoyl]piperazinedihydrochloride (D28) and the appropriate acid chloride using the methodof Example 59 and displayed ¹H NMR and mass spectral data that wereconsistent with structure.

Example Mass Spectrum No R^(X) (ES⁺) E123

[M + H]⁺ 454 E124

[M + H]⁺ 470

EXAMPLES 125-127 E125-E127

Examples 125-127 were prepared from4-[(1-isopropyl-4-piperidinyl)oxy]benzoyl]piperazine dihydrochloride(D38) and the appropriate acid chloride using the method of Example 59and displayed ¹H NMR and mass spectral data that were consistent withstructure.

Example Mass Spectrum No R^(X) (ES⁺) E125

[M + H]⁺ 442 E126

[M + H]⁺ 426 E127

[M + H]⁺ 471/473

EXAMPLES 128-131 E128-E131

Examples 128-131 were prepared from4-[(1-isopropyl-4-piperidinyl)oxy]benzoyl]piperazine dihydrochloride(D38) and the appropriate acid using the method of Example 89 anddisplayed ¹H NMR and mass spectral data that were consistent withstructure.

Example Mass Spectrum No R^(X) (ES⁺) E128

[M + H]⁺ 494 E129

[M + H]⁺ 505 E130

[M + H]⁺ 430 E131

[M + H]⁺ 444

EXAMPLES 132-134 E132-E134

Examples 132-134 were prepared from4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl]piperazine dihydrochloride(D37) and the appropriate acid chloride using the method of Example 59and displayed ¹H NMR and mass spectral data that were consistent withstructure.

Example Mass Spectrum No R^(X) (ES⁺) E132

[M + H]⁺ 454 E133

[M + H]⁺ 438 E134

[M + H]⁺ 483/485

EXAMPLES 135-138 E135-E138

Examples 135-138 were prepared from from4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl]piperazine dihydrochloride(D37) and the appropriate acid using the method of Example 89 exceptthat DMF was used as solvent and displayed ¹H NMR and mass spectral datathat were consistent with structure.

Example Mass Spectrum No R^(X) (ES⁺) E135

[M + H]⁺ 506 E136

[M + H]⁺ 517 E137

[M + H]⁺ 442 E138

[M + H]⁺ 456

EXAMPLES 139-142 E139-E142

Examples 139-142 were prepared from4-[(1-cyclopentyl-4-piperidinyl)oxy]benzoyl]piperazine dihydrochloride(D39) and the appropriate acid chloride using the method of Example 59and displayed ¹H NMR and mass spectral data that were consistent withstructure.

Example Mass Spectrum No R^(X) (ES⁺) E139

[M + H]⁺ 468 E140

[M + H]⁺ 452 E141

[M + H]⁺ 497/499 E142

[M + H]⁺ 455

EXAMPLES 143-146 E143-146

Examples 143-146 were prepared from from4-[(1-cyclopentyl-4-piperidinyl)oxy]benzoyl]piperazine dihydrochloride(D39) and the appropriate acid using the method of of Example 89 exceptthat DMF was used as solvent and displayed ¹H NMR and mass spectral datathat were consistent with structure.

Example Mass Spectrum No R^(X) (ES⁺) E143

[M + H]⁺ 520 E144

[M + H]⁺ 531 E145

[M + H]⁺ 456 E146

[M + H]⁺ 470

EXAMPLE 147 N-[4-(3-Piperldin-1-ylpropoxy)benzoyl]-4-phenylpiperidineHydrochloride (E147)

A solution of 4-(3-piperidin-1-ylpropoxy)benzoic acid hydrochloride(D2)(150 mg) in thionyl chloride (2 ml) was refluxed for 1 h, cooled tort and evaporated. The acid chloride was re-evaporated from DCM (2×3ml). The residue was redissolved in DCM (5 ml) and triethylamine (0.21ml) and added to a stirred solution of 4-phenylpiperidine (81 mg) in DCM(2 ml) at rt. The mixture was stirred for 1 h and then chromatographed(silica gel, step gradient 4-8% MeOH in DCM). Fractions containing therequired product were treated with excess hydrogen chloride (4M solutionin dioxan) and then concentrated to yield the title compound (E147) (173mg). MS electrospray (+ ion) 407 (MH⁺). ¹H NMR a (DMSO-d₆): 10.29 (1H,s), 7.41 (2H, d, J=8.5 Hz), 7.28 (5H, m), 6.99 (2H, d, J=8.5 Hz), 4.10(2H, t, J=6.5 Hz), 2.70-3.53 (11H, m), 2.24 (2H, m), 1.30-1.85 (10H, m).

EXAMPLE 148N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-4-(4-phenyl-1,3-dihydroimidazol-2-one-1-yl)piperidineHydrochloride (E148)

4-(3-Piperidin-1-ylpropoxy)benzoic acid hydrochloride (D2) (49 mg) wasconverted to the title compound (E148) by reaction with4-phenyl-1,3-dihydroimidazol-2-one-1-ylpiperidine (Carling et al., J.Med. Chem., 1999, 42, 2706) (40 mg) using the method described inExample 1 (E1) (yield=73 mg). MS electrospray (+ ion) 490 (MH⁺). ¹H NMRδ (DMSO-d6): 10.73 (1H, s), 9.58 (1H, s), 6.96-7.55 (10H, m), 4.14 (2H,t, J=6 Hz), 3.25-3.77 (9H, m), 2.90 (2H, m), 2.17 (2H, m), 1.13-1.89(10H, m).

EXAMPLE 149 N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]piperidineHydrochloride (E149)

A solution of 4-(3-piperidin-1-ylpropoxy)benzoic acid hydrochloride (D2)(227 mg) in DMF at rt was treated with Argonaut PS Carbodiimide resin(778 mg, 1.3 mmol/g) and stirred for 5 min. Piperidine (0.05 ml) wasadded and the mixture stirred overnight, filtered and evaporated. Theresidue was partitioned between EtOAc (10 ml) and saturated sodiumhydrogen carbonate solution (5 ml). The organic phase was collected,washed with water (3×), saturated brine, dried (MgSO₄) treated withexcess hydrogen chloride (4M in dioxan) and evaporated to yield thetitle compound (E149) (72 mg). MS electrospray (+ ion) 331 (MH⁺). ¹H NMRδ (DMSO-d₆): 10.30 (1H, s), 7.33 (2H,d,J=8.8 Hz), 6.97 (2H,d,J=8.8 Hz),4.10 (2H, t, J=6 Hz), 2.75-3.70 (10H, m), 2.20 (2H, m), 1.25-1.91 (12H,m).

EXAMPLES 150-151 E150-151

Examples 150-151 were prepared from 4-(3-piperidin-1-ylpropoxy)benzoicacid hydrochloride (D2) and the appropriate amine using the methodoutlined in Example 147 (E1) and displayed ¹H NMR and mass spectral datathat were consistent with structure.

Example Mass Spectrum No R^(X) (ES⁺) E150

345 [M + H]⁺ E151

359 [M + H]⁺

EXAMPLE 152 E152

Example 152 was prepared from 4-(3-piperidin-1-ylpropoxy)benzoic acidhydrochloride (D2) and 4-hydroxy-4-phenylpiperidine using the methodoutlined in Example 147 (E147) with the exception that polymer supportedbase was employed. ¹H NMR and mass spectral data were consistent withstructure.

Example No R^(X) Mass Spectrum E152

423 [M + H]⁺

EXAMPLE 153 N-[2-Fluoro-4-(3-piperidin-1-ylpropoxy)benzoyl]piperidinehydrochloride (E153)

The title compound (E153) was prepared from2-fluoro-4-(3-piperidin-1-ylpropoxy)benzoyl chloride hydrochloride (D22)and piperidine using the method described in Example 59. MS electrospray(+ ion) 349 (MH⁺)

EXAMPLE 154N-[2,5-Difluoro-4-(3-piperidin-1-ylpropoxy)benzoyl]piperidineHydrochloride (E154)

The tile compound (E154) was prepared from2,5-difluoro-4-(3-piperidin-1-ylpropoxy)benzoyl chloride hydrochloride(D19) and piperidine using the method described in Example 59. MSelectrospray (+ ion) 367 (MH⁺)

EXAMPLE 155N-[2-Trifluoromethyl-4-(3-Piperidin-1-ylpropoxy)benzoyl]piperidineHydrochloride (E155)

The tile compound (E155) was prepared from4-(3-piperidin-1-yl-propoxy)-2-trifluoromethyl-benzoyl chloridehydrochloride (D16) and piperidine using the method described in Example59. MS electrospray (+ ion) 399 (MH⁺)

EXAMPLE 156(S)-N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-3-benzamidopyrrolidineDihydrochloride (E156)

A stirred solution of(S)-N-[4-(3-piperidin-1-ylpropoxy)benzoyl]-3-aminopyrrolidinedihydrochloride (D11) (134 mg) and triethylamine (0.18 ml) in DCM at rtwas treated with benzoyl chloride (0.046 ml). After 2 h the mixture waswashed with saturated sodium hydrogen carbonate solution (5 ml), water(3×5 ml), dried (MgSO₄) and evaporated. The residue was chromatographed(silica gel, step gradient 0-20% MeOH in DCM). Fractions containing therequired product were treated with excess hydrogen chloride (4M solutionin dioxan) and then concentrated to yield the title compound (E156) (56mg). MS electrospray (+ ion) 436 (MH⁺).¹H NMR δ (DMSO-d₆) at 353° K.:10.15 (1H,s), 8.30 (1H,d,J=5.5 Hz), 7.82 (2H,d,J=8 Hz), 7.45 (5H,m),6.97 (2H,d,J=8 Hz), 4.45 (1H,m), 4.12 (2H,t,J=6 Hz), 3.68 (2H,s),2.80-3.90 (11H, m), 2.90 (2H,m), 2.18 (2H,m), 1.38-2.35 (6H,m).

EXAMPLE 157N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-(R,S)-2-phenylpyrrolidineHydrochloride (E157)

A solution of 4-(3-piperidin-1-ylpropoxy)benzoic acid hydrochloride (D2)(299 mg) in thionyl chloride (8 ml) was refluxed for 1 h, cooled to rtand evaporated. The acid chloride was re-evaporated from DCM (2×5 ml).The residue was redissolved in DCM (15 ml) and triethylamine (0.43 ml)and added to a stirred solution of (R,S)-2-phenylpyrrolidine (147 mg) inDCM (5 ml) at rt. The mixture was stirred for 1 h, washed with saturatedsodium hydrogen carbonate solution (10 ml), water (3×10 ml), dried(MgSO₄) and evaporated. The residue was chromatographed (silica gel,step gradient 2-7% MeOH (containing 10% 0.880 ammonia solution) in DCM).Fractions containing the required product were treated with excesshydrogen chloride (4M solution in dioxan) and then concentrated to yieldthe title compound (E157) (332 mg). MS electrospray (+ ion) 393 (MH⁺).¹H NMR δ (DMSO-d6): at 353° K. 10.20 (1H, s), 7.40 (2H, d, J=8.5 Hz),7.25 (5H, m), 6.89(2H, d, J=8.5 Hz), 5.11 (1H, m), 4.09 (2H, t, J=6.5Hz), 2.80-3.83 (6H, m), 2.05-2.55 (6H, m), 1.31-1.93 (8H, m).

EXAMPLE 158(S)-N-[4-(3-Piperidin-1-ylpropoxy)benzoyl]-3-(naphthalene-1-carboxamidopyrrolidinedihydrochloride (E158)

The title compound (E158) was prepared from(S)-N-[4-(3-piperidin-1-ylpropoxy)benzoyl]-3-aminopyrrolidinedihydrochloride (D11) and 1-naphthoyl chloride using the method outlinedin Example 156. MS electrospray (+ ion) 486 (MH⁺). ¹H NMR dataconsistent with structure.

EXAMPLE 1594-Phenyl-9-[4-(3-piperidin-1-ylpropoxy)benzoyl]-1-oxa-4,9-diazaspiro-[5,5]-undecan-3-onehydrochloride (E159)

A solution of 4-(3-piperidin-1-ylpropoxy)benzoic acid hydrochloride (D2)(97 mg) in thionyl chloride (2.6 ml) was refluxed for 1 h, cooled to rtand evaporated. The acid chloride was re-evaporated from DCM (2×3 ml).The residue was redissolved in DCM (5 ml) and triethylamine (0.14 ml)and added to a stirred solution of4-phenyl-1-oxa-4,9-diazaspiro-[5,5]-undecan-3-one (80 mg) (Caroon etal., J. Med. Chem., 1981, 24, 1320) in DCM (2 ml) at rt. The mixture wasstirred for 1 h, washed with saturated sodium hydrogen carbonatesolution (5 ml), water (3×5 ml), dried (MgSO₄) and evaporated. Theresidue was chromatographed [silica gel, step gradient 0-5% MeOH(containing 10% of 0.880 ammonia solution) in DCM]. Fractions containingthe required product were treated with excess hydrogen chloride (4Msolution in dioxan) and then concentrated to yield the title compound(E159) (79 mg). MS electrospray (+ ion) 492 (MH⁺). ¹H NMR δ (DMSO-d6):9.77 (1H, s), 6.98-7.44 (9H, m), 4.25 (2H, s), 4.10 (2H, t, J=6 Hz),3.68 (2H, s), 3.05-3.78 (8H, m), 2.90 (2H, m), 2.18 (2H, m), 1.28-2.05(10H, m).

EXAMPLE 1603-Benzyl-8-[4-(3-piperidin-1-ylpropoxy)benzoyl]-1,3,8-triaza-spiro[4.5]-decan-2-one(E160)

4-(3-Piperidin-1-ylpropoxy)benzoic acid hydrochloride (D2) (49 mg) wasconverted to the title compound (E160) by reaction with3-benzyl-1,3,8-triaza-spiro[4.5]decan-2-one (Smith et al., J. Med.Chem., 1995, 38, 3772) (40 mg) using the method described in Example 159(E159) with the exception that the product was isolated as the freebase. (yield=47 mg). MS electrospray (+ ion) 491 (MH⁺). ¹H NMR δ(CDCl₃): 6.86-7.42 (9H, m), 4.88 (1H, s), 4.39 (2H, s), 4.00 (2H, t,J=6.4 Hz), 3.65 (4H, m), 3.14 (2H, s), 2.45 (2H, m), 1.98 (2H, m),1.37-1.82 (10H, m).

EXAMPLES 161-162 E161-162

Examples 161-162 were prepared from 4-(3-piperidin-1-ylpropoxy)benzoicacid hydrochloride (D2) and the appropriate amine using the methodoutlined in Example 159 (E159) and displayed ¹H NMR and mass spectraldata that were consistent with structure.

Example Mass Spectrum No R^(X) (ES⁺) E161

431 [M + H]⁺ E162

478 [M + H]⁺

EXAMPLE 163 N-[4-(3-Piperidin-1-ylpropoxy)benzenesulfonyl]morpholineHydrochloride (E163)

A solution of 4-[4-(3-bromopropoxy)benzenesulfonyl]morpholine (D13) (96mg) in 1-butanol (5 ml) and piperidine (0.22 ml) was heated at 100° C.for 16 h, cooled to rt and evaporated. The residue was redissolved inEtOAc (10 ml), washed with saturated sodium hydrogen carbonate solution(5 ml), water (3×5 ml), dried (MgSO₄) and evaporated. The residue wasredissolved in DCM and treated with excess hydrogen chloride (4Msolution in dioxan) and then concentrated to yield the title compound(E163) (75 mg). MS electrospray (+ ion) 369 (MH⁺). ¹H NMR δ (DMSO-d₆):10.21 (1H, s), 7.68 (2H, d, J=8.8 Hz), 7.18 (2H, d, J=8.8 Hz), 4.18 (2H,t, J=6 Hz), 3.62 (2H, m), 3.44 (2H, m), 3.17 (2H, m), 2.84 (6H, m),1.30-1.85 (6H, m).

EXAMPLES 164-168 E164-168

Examples 164-168 were prepared from the appropriate amine using ananalogous method to that described in Description 13 (D13) followed byExample 163 (E163). All compounds displayed ¹H NMR and mass spectraldata that were consistent with structure.

Example No R^(X)R^(Y)N Mass Spectrum E164

367 [M + H]⁺ E165

443 [M + H]⁺ E166

401 [M + H]⁺ E167

401 [M + H]⁺ E168

444 [M + H]⁺

EXAMPLE 169 N-[4-(3-Piperidin-1-ylpropoxy)benzenesulfonyl]piperazinedihydrochloride (E169)

The title compound (E169) was prepared using an analogous method to thatdescribed in Description 13 (D13) followed by Example 163 (E163) bytreating N-Boc piperazine with1-bromo-3-(4-chlorosulfonylphenoxy)propane followed by reaction withpiperidine. Subsequent deprotection with HCl afforded thedihydrochloride salt. MS electrospray (+ ion) 368 (MH⁺).

EXAMPLES 170-171 E170-171

Examples 170-171 were prepared from Example 169 (E169) by treatment withthe appropriate acid chloride in the presence of triethylamine using DCMas solvent.

Example No R^(X)R^(Y)N Mass Spectrum E170

522 [M + H]⁺ E171

556 [M + H]⁺

EXAMPLE 1721-[4-(3-Piperldin-1-ylpropoxy)benzoyl]-4-t-butoxycarbonylhomopiperazine(E172)

To t-butoxycarbonylhomopiperazine (0.76 g) in DCM (10 ml) was addedtriethylamine (1.2 ml) and the mixture was cooled to 0° C. followed bythe slow addition of 4-(3-piperidin-1-ylpropoxy)benzoyl chloridehydrochloride (D3) (1.2 g) in DCM (10 ml). The mixture was stirred at rtfor 3 h, then washed with water. The organic layer was dried (MgSO₄) andevaporated to give the title compound (E172) as a cream coloured solid(1.69 g).

Mass Spectrum 446 [M+H]⁺

Abbreviations

-   Boc tertbutoxycarbonyl-   EtOAc ethyl acetate-   h hour-   DCM dichloromethane-   MeOH methanol-   rt room temperature-   DCC dicyclohexylcarbodiimide-   DMF dimethylformamide

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

Biological Data

A membrane preparation containing histamine H3 receptors may be preparedin accordance with the following procedures:

(i) Generation of Histamine H3 Cell Line

DNA encoding the human histamine H3 gene (Huvar, A. et al. (1999) Mol.Pharmacol. 55(6), 1101-1107) was cloned into a holding vector, pcDNA3.1TOPO (InVitrogen) and its cDNA was isolated from this vector byrestriction digestion of plasmid DNA with the enzymes BamHI and Not-1and ligated into the inducible expression vector pGene (InVitrogen)digested with the same enzymes. The GeneSwitch™ system (a system wherein transgene expression is switched off in the absence of an inducer andswitched on in the presence of an inducer) was performed as described inU.S. Pat. Nos. 5,364,791; 5,874,534; and 5,935,934. Ligated DNA wastransformed into competent DH5α E. coli host bacterial cells and platedonto Luria Broth (LB) agar containing Zeocin™ (an antibiotic whichallows the selection of cells expressing the sh ble gene which ispresent on pGene and pSwitch) at 50 μg ml⁻¹. Colonies containing thereligated plasmid were identified by restriction analysis. DNA fortransfection into mammalian cells was prepared from 250 ml cultures ofthe host bacterium containing the pGeneH3 plasmid and isolated using aDNA preparation kit (Qiagen Midi-Prep) as per manufacturers guidelines(Qiagen).

CHO K1 cells previously transfected with the pSwitch regulatory plasmid(InVitrogen) were seeded at 2×10e6 cells per T75 flask in CompleteMedium, containing Hams F12 (GIBCOBRL, Life Technologies) mediumsupplemented with 10% v/v dialysed foetal bovine serum, L-glutamine, andhygromycin (100 μg ml⁻¹), 24 hours prior to use. Plasmid DNA wastransfected into the cells using Lipofectamine plus according to themanufacturers guidelines (InVitrogen). 48 hours post transfection cellswere placed into complete medium supplemented with 500 μg ml⁻¹ Zeocin™.

10-14 days post selection 10 nM Mifepristone (InVitrogen), was added tothe culture medium to induce the expression of the receptor. 18 hourspost induction cells were detached from the flask using ethylenediaminetetra-acetic acid (EDTA; 1:5000; InVitrogen), following several washeswith phosphate buffered saline pH 7.4 and resuspended in Sorting Mediumcontaining Minimum Essential Medium (MEM), without phenol red, andsupplemented with Earles salts and 3% Foetal Clone II (Hyclone).

Approximately 1×10e7 cells were examined for receptor expression bystaining with a rabbit polyclonal antibody, 4a, raised against theN-terminal domain of the histamine H3 receptor, incubated on ice for 60minutes, followed by two washes in sorting medium.

Receptor bound antibody was detected by incubation of the cells for 60minutes on ice with a goat anti rabbit antibody, conjugated with Alexa488 fluorescence marker (Molecular Probes). Following two further washeswith Sorting Medium, cells were filtered through a 50 μm Filcon™ (BDBiosciences) and then analysed on a FACS Vantage SE Flow Cytometerfitted with an Automatic Cell Deposition Unit. Control cells werenon-induced cells treated in a similar manner. Positively stained cellswere sorted as single cells into 96-well plates, containing CompleteMedium containing 500 μg ml⁻¹ Zeocin™ and allowed to expand beforereanalysis for receptor expression via antibody and ligand bindingstudies. One clone, 3H3, was selected for membrane preparation.

(ii) Membrane Preparation from Cultured Cells

All steps of the protocol are carried out at 4° C. and with pre-cooledreagents. The cell pellet is resuspended in 10 volumes of buffer A2containing 50 mM N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid(HEPES) (pH 7.40) supplemented with 10e4M leupeptin(acetyl-leucyl-leucyl-arginal; Sigma L2884), 25 μg/ml bacitracin (SigmaB0125), 1 mM ethylenediamine tetra-acetic acid (EDTA), 1 mMphenylmethylsulfonyl fluoride (PMSF) and 2×10e-6M pepstain A (Sigma).The cells are then homogenised by 2×15 second bursts in a 1 litre glassWaring blender, followed by centrifugation at 500 g for 20 minutes. Thesupernatant is then spun at 48,000 g for 30 minutes. The pellet isresuspended in 4 volumes of buffer A2 by vortexing for 5 seconds,followed by homogenisation in a Dounce homogeniser (10-15 strokes). Atthis point the preparation is aliquoted into polypropylene tubes andstored at −70° C.

Compounds of the invention may be tested for in vitro biologicalactivity in accordance with the following assays:

(I) Histamine H3 Binding Assay

For each compound being assayed, in a white walled clear bottom 96 wellplate, is added:

-   (a) 10 μl of test compound (or 10 μl of iodophenpropit (a known    histamine H3 antagonist) at a final concentration of 10 mM) diluted    to the required concentration in 10% DMSO;-   (b) 10 μl ¹²⁵I 4-[3-(4-iodophenylmethoxy)propyl]-1H-imidazolium    (iodoproxyfan) (Amersham; 1.85 MBq/μl or 50 μCi/ml; Specific    Activity ˜2000Ci/mmol) diluted to 200 pM in assay buffer (50 mM    Tris(hydroxymethyl)aminomethane buffer (TRIS) pH 7.4, 0.5 mM    ethylenediamine tetra-acetic acid (EDTA)) to give 20 pM final    concentration; and-   (c) 80 μl bead/membrane mix prepared by suspending Scintillation    Proximity Assay (SPA) bead type WGA-PVT at 100 mg/ml in assay buffer    followed by mixing with membrane (prepared in accordance with the    methodology described above) and diluting in assay buffer to give a    final volume of 80 μl which contains 7.5 μg protein and 0.25 mg bead    per well—mixture was pre-mixed at room temperature for 60 minutes on    a roller. The plate is shaken for 5 minutes and then allowed to    stand at room temperature for 3-4 hours prior to reading in a Wallac    Microbeta counter on a 1 minute normalised tritium count protocol.    Data was analysed using a 4-parameter logistic equation.    (II) Histamine H3 Functional Antagonist Assay

For each compound being assayed, in a white walled clear bottom 96 wellplate, is added:—

-   (a) 10 μl of test compound (or 10 μl of guanosine 5′-triphosphate    (GTP) (Sigma) as non-specific binding control) diluted to required    concentration in assay buffer (20 mM    N-2-Hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES)+100 mM    NaCl+10 mM MgCl₂, pH7.4 NaOH);-   (b) 60 μl bead/membrane/GDP mix prepared by suspending wheat germ    agglutinin-polyvinyltoluene (WGA-PVT) scintillation proximity assay    (SPA) beads at 100 mg/ml in assay buffer followed by mixing with    membrane (prepared in accordance with the methodology described    above) and diluting in assay buffer to give a final volume of 60 μl    which contains 10 μg protein and 0.5 mg bead per well—mixture is    pre-mixed at 4° C. for 30 minutes on a roller and just prior to    addition to the plate, 10 μM final concentration of guanosine 5′    diphosphate (GDP) (Sigma; diluted in assay buffer) is added; The    plate is incubated at room temperature to equilibrate antagonist    with receptor/beads by shaking for 30 minutes followed by addition    of:-   (c) 10 μl histamine (Tocris) at a final concentration of 0.3 μM; and-   (d) 20 μl guanosine 5′[γ35-S] thiotriphosphate, triethylamine salt    (Amersham; radioactivity concentration=37 kBq/μl or 1 mCi/ml;    Specific Activity 1160 Ci/mmol) diluted to 1.9 nM in assay buffer to    give 0.38 nM final.

The plate is then incubated on a shaker at room temperature for 30minutes followed by centrifugation for 5 minutes at 1500 rpm. The plateis read between 3 and 6 hours after completion of centrifuge run in aWallac Microbeta counter on a 1 minute normalised tritium countprotocol. Data is analysed using a 4-parameter logistic equation. Basalactivity used as minimum i.e. histamine not added to well.

Results

The compounds of Examples E1-E103 and E105-E172 were tested in thehistamine H3 functional antagonist assay and exhibited pK_(b)values >7.5. More particularly, the compounds of Examples E1-3, E5-7,E9, Eli, E13-16, E18-19, E21-25, E28, E30, E33, E35, E3741, E47, E49,E51-53, E57, E59-61, E63-65, E67-68, E72, E75, E78, E80, E84-86, E88-89,E93-94, E96, E98, E99-E101, E107-108, E110-111, E115-119, E121-122,E123, E125, E128-131, E132-138, E139-146, E149-151, E155-160, E162,E164-165, E170 exhibited pK_(b) values >8.5.

1. A compound of formula (I) or a pharmaceutically acceptable saltthereof:

wherein: R¹ represents a group of formula (A):

wherein R^(4a) represents C₁₋₆ alkyl, oxo, aryl, heteroaryl orheterocyclyl; R^(5a) represents hydrogen, -C₁ alkyl, -C₁₋₆ alkylC₁₋₆alkoxy, -C₁₋₆ alkoxycarbonyl, -C₃₋₈ cycloalkyl, -aryl, -heterocyclyl,heteroaryl, -C₁ alkyl-aryl, —CH(aryl)(aryl), -C₁₋₆ alkyl-C₃₋₈cycloalkyl, -C₁₋₆ alkyl-heteroaryl or -C₁ alkyl-heterocyclyl, whereinR^(5a) may be optionally substituted by one or more substituents whichmay be the same or different, and which are selected from the groupconsisting of halogen, hydroxy, cyano, nitro, oxo, haloC₁₋₆ alkyl,polyhaloC₁₋₆ alkyl, haloC₁₋₆ alkoxy, polyhaloC₁₋₆alkoxy, C₁₋₆ alkyl,C₁₋₆alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkoxyC₁₋₆ alkyl, C₃₋₇ cycloalkylC₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylsulfonyl,C₁-alkylsulfinyl, C₁₋₆ alkylsulfonyloxy, C₁₋₆ alkylsulfonylC₁₋₆ alkyl,C₁₋₆alkylsulfonamidoC₁₋₆alkyl, C₁₋₆ alkylamidoC₁₋₆alkyl or a groupNR^(15a)R^(16a), —CONR^(15a)R^(16a), —NR^(15a)COR^(16a),—NR^(15a)SO₂R^(16a) or —SO₂NR^(15a)R^(16a), wherein R^(15a) and R^(16a)independently represent hydrogen, C₁₋₆ alkyl, aryl or together with thenitrogen to which they are attached may form a nitrogen containingheterocyclyl group; m is 1 or 2; p is 0, 1, 2 or 3, or when p represents2, said R^(4a) groups may instead form a bridging group consisting ofone or two methylene groups; or R¹ represents a group of formula (B):

wherein NR^(4b)R^(5b) represents an N-linked -heterocyclyl,-heterocyclyl-X^(b)-aryl, -heterocyclyl-X^(b)-heteroaryl,-heterocyclyl-X^(b)-heterocyclyl, -heteroaryl, -heteroaryl-X^(b)-aryl,-heteroaryl-X^(b)-heteroaryl or -heteroaryl-X^(b)-heterocyclyl group;wherein said aryl, heteroaryl and heterocyclyl groups of NR^(4b)R^(5b)may be optionally substituted by one or more substituents which may bethe same or different, and which are selected from the group consistingof halogen, hydroxy, cyano, nitro, oxo, haloC₁₋₆ alkyl, polyhaloC₁₋₆alkyl, haloC₁₋₆ alkoxy, polyhaloC₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkoxy,arylC₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkoxyC₁₋₆ alkyl, C₃₋₇cycloalkylC₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆ alkoxycarbonyl, arylC₁₋₆ alkyl,heteroarylC₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyloxy, C₁₋₆ alkylsulfonylC₁₋₆ alkyl, arylsulfonyl,arylsulfonyloxy, arylsulfonylC₁₋₆ alkyl, aryloxy, C₁₋₆alkylsulfonamidoC₁₋₆ alkyl, C₁₋₆ alkylamidoC₁₋₆ alkyl, arylsulfonamido,arylaminosulfonyl, arylsulfonamidoC₁₋₆ alkyl, arylcarboxamidoC₁₋₆ alkyl,aroylC₁₋₆ alkyl, arylC₁₋₆ alkanoyl, or a group —NR^(15b)R^(16b),—CONR^(15b)R^(16b), —NR^(5b)COR^(16b), —NR^(15b)SO₂R^(16b) or—SO₂NR^(15b)R^(16b), wherein R^(15b) and R^(16b) independently representhydrogen or C₁₋₆alkyl; X^(b) represents a bond, CO, NHCO or CONH; or R¹represents a group of formula (C):

wherein R^(4c) represents C₁₋₆ alkyl, OH, aryl or heterocyclyl, whereinsaid aryl and heterocyclyl groups may be optionally substituted byhalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cyano, amino, oxo, trifluoromethyl oran aryl group; r is 0, 1 or 2; or R¹ represents a group of formula (D):

wherein R^(4d) represents aryl or heteroaryl wherein said aryl andheteroaryl groups may be optionally substituted by one or moresubstituents which may be the same or different, and which are selectedfrom the group consisting of halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cyano,amino or trifluoromethyl; X^(d) represents a bond or NHCO, such thatwhen X^(d) represents NHCO, the group R^(4d)—X^(d) is attached at the3-position of the pyrrolidinyl ring; or R¹ represents a group of formula—CO-E, wherein E represents a group of formula E^(a), E^(b) or E^(c):

wherein X^(e) represents O or N—R^(8e); Y^(e) represents —C(HR^(9e))— or—C(═O)—; R^(4e), R^(5e), R^(8e) and R^(9e) independently representhydrogen, C₁ alkyl, aryl, heteroaryl, —C₁₋₆alkyl-aryl or-C₁₋₆alkyl-heteroaryl; R^(6e) and R^(7e) independently representhydrogen, C₁₋₆ alkyl, aryl, heteroaryl, -C₁₋₆ alkyl-aryl, -C₁₋₆alkyl-heteroaryl or R^(6e) and R^(7e) together with the carbon atoms towhich they are attached may form a benzene ring;

is a single or double bond; wherein said aryl or heteroaryl groups ofR^(4e), R^(5e), R^(6e), R^(7e) and R^(9e) may be optionally substitutedby one or more substituents which may be the same or different, andwhich are selected from the group consisting of C₁₋₆ alkyl, CF₃, C₁₋₆alkoxy, halogen, cyano, sulfonamide or C₁₋₆ alkylsulfonyl; or R¹represents a group of formula (F):

wherein t is 0, 1 or 2; u is 1 or 2; R^(4f) represents C₁₋₆ alkyl orwhen t represents 2, said R^(4f) groups may instead form a bridginggroup consisting of one or two methylene groups; R^(5f) represents -C₁₋₆alkyl, -C₁₋₆ alkylC₁₋₆alkoxy, -C₁₋₆ cycloalkyl, aryl, heterocyclyl,heteroaryl, -C₁₋₆ alkyl-aryl, -C₁₋₆ alkyl-C₃₋₈ cycloalkyl, -C₁₋₆alkyl-heteroaryl, -C₁₋₆ alkyl-heterocyclyl, -aryl-aryl,-aryl-heteroaryl, -aryl-heterocyclyl, -heteroaryl-aryl,-heteroaryl-heteroaryl, -heteroaryl-heterocyclyl, -heterocyclyl-aryl,-heterocyclyl-heteroaryl or -heterocyclyl-heterocyclyl; wherein R^(5f)may be optionally substituted by one or more substituents which may bethe same or different, and which are selected from the group consistingof halogen, hydroxy, cyano, nitro, oxo, haloC₁₋₆alkyl,polyhaloC₁₋₆alkyl, haloC₁₋₆alkoxy, polyhaloC₁₋₆alkoxy, C₁— alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkoxyC₁₋₆alkyl, C₃₋₇cycloalkylC₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkoxycarbonyl,C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyloxy,C₁₋₆alkylsulfonylC₁₋₆alkyl, C₁₋₆alkylsulfonamidoC₁₋₆alkyl,C₁₋₆alkylamidoC₁₋₆alkyl, arylsulfonyl, arylsulfonyloxy, aryloxy,arylsulfonamido, arylcarboxamido, aroyl, or a group NR^(15f)R^(16f),—CONR^(15f)R¹⁶f, —NR^(15f)COR^(16f), —NR¹⁵SO₂R^(16f) or—SO₂NR^(15f)R^(16f), wherein R^(15f) and R^(16f) independently representhydrogen or C₁₋₆alkyl or together form a heterocyclic ring; Z^(f)represents CO or SO₂; R² represents halogen, C₁₋₆alkyl, C₁₋₆alkoxy,cyano, amino or trifluoromethyl; n is 0, 1 or 2; R³ represents—(CH₂)_(q)—NR¹¹R¹² or a group of formula (i):

wherein q is 2, 3 or 4; R¹¹ and R¹² independently represent C₁₋₆alkyl ortogether with the nitrogen atom to which they are attached represent anN-linked heterocyclic group selected from pyrrolidine, piperidine andhomopiperidine optionally substituted by one or two R¹⁷ groups; R¹³represents C₁₋₆alkyl, C₃₋₆ cycloalkyl or -C₁₋₆ alkyl-C₃₋₆cycloalkyl; R¹⁴and R¹⁷ independently represent halogen, C₁₋₆alkyl, haloC₁₋₆ alkyl, OH,diC₁₋₆ alkylamino or C₁— alkoxy; f and k independently represent 0, 1 or2; g is 0, 1 or 2 and h is 0, 1, 2 or 3, such that g and h cannot bothbe 0; or solvates thereof.
 2. A compound according to claim 1 which is acompound selected from the group consisting of E1-E172 or apharmaceutically acceptable salt thereof.
 3. A pharmaceuticalcomposition which comprises the compound of formula (I) as defined inclaim 1 or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier or excipient. 4-6. (canceled)
 7. Amethod of treatment of neurological diseases which comprisesadministering to a host in need thereof an effective amount of acompound of formula (I) as defined in claim 1 or a pharmaceuticallyacceptable salt thereof.
 8. (canceled)